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EMBRYOLOGY


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About Embryology and this guide:

This guide is written from Dr. Hills notes. All original work is that of Dr. Hill. These have been written in narrative form and have some minor commentary inserted on top of Dr. Hills information. This guide (and Dr. Hill) requires a working knowledge of Anatomy and Anatomical vocabulary (especially direction). You will be challenged to keep up in lecture, less you prepare ahead of time. It is NOT that Dr. Hill is a poor teacher, or his lectures poorly designed. Rather, Embryology has a vocabulary all its own, one Dr. Hill is fluent in, and one you have not seen. He is correct to the T, which can sometimes be difficult to follow.

Dr. Hill loves detail. His questions are nit picky and detailed. They are hardly ever conceptual and are often taken as a single line from his notes. There is no way of telling exactly what he wants you to know, but know this: DR HILL WILL NEVER ASK YOU ANYTHING HE HAS NOT TAUGHT YOU IN LECTURE. That being the case, unless you really like embryo, Moores embryo book is mostly useless. It can help you understand whats going on, but has so much superfluous detail.

Some of the lectures for this year were presented last year, but did not come with handouts to develop

for this guide. Those lectures marked as (Ghost) in the table of contents have no content. Rather than writing an erroneous guide that may mislead you, I leave it up to your NoteService and lecture recordings to fill in the blanks. Remember that in purchasing this guide you are already enrolled in the Anatomy Trimester of NoteService.

In the true spirit of this guide: Take Away : Embryo is tough to keep pace with in lecture, Dr. Hill is correct to the T and will only ask you what he teaches you, and some of this guide will have to be filled in by your year.

Sincerely,

The Author


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Class PageAug 5 Introduction to Embryology Gametogenesis and Meiosis 1

Aug 6 Fertilzation, Preimplantation, Bilaminary Embryo5Aug 7 Trilaminar Embryo 12Aug 11 Development of Spine and PNS 16Aug 18 Development of Musculoskeletal System 19

Date

EMBRYO


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Embryo - August 5th Introduction to Embryology

| T 1 s f o r D u m m i e s , M a k i n g F i r s t Y e a r a L i t t l e E a s i e r

Gametogenesis

Meiosis the process in which a diploid cell becomes multiple haploid cells by undergoing two subsequent divisions without sequestering and the chance to reduplicate the genetic material. Spermiogenesis the last leg in the trip of spermatogenesis whereby haploid spermatids are manipulated and turned into spermatozoa (in the seminiferous tubules). Spermatogenesis the steps in which a spermatogonia (germ cell) is transformed into a spermatozoa. Oogenesis gametogenesis for eggs Primary Spermatocyte / Oocyte diploid stage after mitosis; ready to undergo meiosis Secondary Spermatocyte / Oocyte haploid stage after meiosis 1. Chromatid one of two genetically identical Strands that make up a chromosome. Chromosome genetic material that codes for a gene Nondisjunction the action in which homologous chromosomes do not separate during meiosis 1 or chromatids do not separate in meiosis 2. Post Zygotic Nondisjunction failure of normal mitosis to separate sister chromatids, resulting in an abnormal distribution of chromosomes equaling a mosaic. Mosaic if a PZN occurs during fetal development, all daughter cells would hence be disrupted. However, all normal cells up to that point would likewise continue to divide, so there would be a mixture, a mosaic, of normal cells and abnormal cells, resulting in a combination of phenotypes. Polar Body Asymmetrical cell division leads to the production of polar bodies during oogenesis. To conserve nutrients, the majority of cytoplasm is segregated into either the secondary oocyte or ovum, during meiosis I or meiosis II, respectively. The remaining daughter cells generated from the meiotic events contain relatively little cytoplasm and are referred to as polar bodies. Eventually, the polar bodies degenerate.

FIVE PHASES OF PROPHASE: (1) Leptotene During this stage, individual chromosomes begin to condense into long strands within the nucleus. However, the two sister chromatids are still so tightly bound that they are indistinguishable from one another. (2) Zygotene Occurs as the chromosomes approximately line up with each other into homologous chromosomes. (3) Pachytene contains the chromosomal crossover. Non sister chromatids of homologous chromosomes randomly exchange segments of genetic information over regions of homology (4) Diplotene the synaptonemal complex degrades and homologous chromosomes separate from one another a little. (5) Diakinesis This is the first point in meiosis where the four parts of the tetrads are actually visible.

Homologous Chromosome each person has two sets of chromosomes, one paternal and one maternal, each that code for the same genes. These are homologous chromosomes. During mitosis, homologous chromosomes do not pair so that daughter cells receive BOTH homologues. In meiosis I, homologous pairs align and separate from one another, leaving only one set of each in daughter cells.

Review of Meiosis: Genetic Material, Chromosomes and Chromatids:

This is a CONCEPTUAL MODEL. Technically a chromatid is no longer a chromatid when it is separated from its centromere (at that point two chromosomes are formed). But to help understand what is happening with what structure, this model is devised.

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The model shows an organism with two chromosomes, red and green. Each has an initial content of a maternally inherited green and red, and a paternally inherited green and red. Green codes from gene G and red codes for gene R. Pay attention to the number of CHROMOSOMES (ploidy) versus the number of CHROMATIDS (genetic content)

In Mitosis the end product is two daughter cells, each with the same number of chromosomes and chromatids, genetically identical to one another. The process is simply:

4 Chromosomes ( diploid) 4 Chromosomes (diploid) 4 Chromosomes each (diploid) 4 Chromatids 8 Chromatids 4 Chromatids each Genetic Material 1x Genetic Material 2x Genetic Material Total 2x, each 1x

In Meiosis I, rather than having all chromosomes align on the metaphyseal plates and separate chromatids from one another, homologous chromosomes align and are pulled apart. Thusly, there is the same amount of total genetic material (total) in each of the products of meiosis 1 as in mitosis, but the genetic composition is vastly different. That is, only one chromosome (either paternal or maternal) for each gene is present.

4 Chromosomes (diploid) 4 Chromosomes (diploid) 2 Chromosomes each (haploid) 4 Chromatids 8 Chromatids 4 Chromatids each Genetic Material 1x Genetic Material 2x Genetic Material Total 2x, 1x each

In meiosis II, the now haploid cells with 4 chromatids worth of genetic material are split into haploid cells with half the genetic content AND half the chromosomes as their original parent. This process is analogous to the process of mitosis (the chromosomes have already duplicated into 2x chromatids), but has only half the genetic material (mitosis would have both sets of homologous chromosomes), so the result is a haploid individual.

2 Chromosomes(haploid) 2 Chromosomes (haploid) 2 Chromosomes each (haploid) 4 Chromatids 4 Chromatids 2 Chromatids each Genetic Material x1 Genetic Material x1 Genetic Material Total 1x, 0.5x each

REMEMBER: THERE IS NO PROPHASE II (the products of meiosis 1 have eliminated that need)

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Spermatogenesis . A diploid cell is converted into 4 haploid cells. The primary spermatocyte remains with the same amount of

genetic material

after

mitosis.

The

secondary

spermatocyte

undergoes

meiosis

I, where

homologous

chromosomes

separate,

leaving the daughter cells haploid. The chromatids separate in meiosis 2, forming spermatids (still haploid). The completion of maturation of the sperm occurs in the seminiferous vesicles. Sperm complete Meiosis 2.

Oogensis . A diploid cell is converted into 1 haploid cell and two or more genetically useless polar bodies . The primary oocyte, which is diploid, undergoes meiosis 1 to form a secondary oocyte and a polar body. Because of the abnormal distribution of cytoplasm into one daughter, the second daughter is insufficient to continue and becomes a dense packet of genetic material. The same is true of the product of meiosis II, following the secondary oocyte to produce the egg. Eggs do not mature until puberty. Oocytes do not complete Meiosis 2 (held in metaphase) until a sperm impregnates the cell membrane with its nucleus

during fertilization.

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Normal Post Zygotic Mitosis . In this cell all Post Zygotic Nondisjunction . After the zygote has performed a chromosomes align along the metaphyseal mitotic division, it is possible for chromatids to fail to separate. plate, and sister chromatids separate to This results in one cell being deficient in a gene and one cell being form normal daughter cells. Triploidy for one gene. It is assumed that in the bold daughter cell

X and one | code for the same gene, which now has 3 copies.

Mosaic a mosaic has a stronger chance of survival because they are created by a post zygotic nondisjunction, and some of their cells are normal, while others have an unequal distribution of genes. They are kind of normal and kind of broken, as opposed to a genetic mishap that happens during the formation of the first cell (the gamete). Pathological phenotypes are reduced in these patients.

See lecture notes for review of pathologies (genetic cause, phenotype, etc.) Im not going to just copy lecture slides, and she didnt spend that much time on them anyway.

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EmbryoAugust 6th: Fertilization, Preimplantation, andDevelopment of the Bilaminar Embryo


This is as concise as you are going to get it. There is very little explanation. Dr. Hill will take questions right out of here, almost word for word. This will not help you understand the material, but it is what you must know.

I. Spermatogenesis & Spermiogenesis development of the sperm:

Begins at puberty. Testes begin to secrete increased amounts of Testosterone, leading to (1) development of secondary sex characteristics (growth, underarm/pubic hair) as well as (2) stimulates growth and development of testes. The development of the testis can be categorized by 4 events: a. maturation of seminiferous tubules b. commencement of Spermatogenesis c. Activity of Sertoli cells supportive cells d. Proliferation of dormant primordial germ cells by mitosis can then differentiate into spermatogonia.

These germ cells leave behind one germ cell and one differentiated spermatogonia.

Spermatogonia themselves are located along basal membrane seminiferous tubules connected to sertoli cell by cytoplasmic bridges.

Spermatogonia undergo spermatogenesis and spermiogenesis. They are not the same thing. Spermatogenesis is the creation of 4 spermatids (spermatogenesis is the creation of spermatids) from one spermatogonia via two rounds of mitosis. Spermatids are immature and cannot do anything yet. Spermiogenesis is the development from spermatid to mature sperm, called spermatozoa .

Spermiogenesis Spermiogenesis is the maturation process from spermatid to mature sperm as germ cells move to the lumen of seminiferous tubules and to the ductus deferens. I wish they kept histology together with embryo, since this makes a ton of sense when you study the histology of the male reproductive

Spermatogonia Spermatid Spermatozoa (mature)SpermiogenesisSpermatogenesis

The basal lamina is the border between everything else and the action of the

testes.

As the germ cells (spermatogonia) undergo divisions,

they ascend, differentiating first into primary then into secondary spermatocytes

Sertoli cells manipulate the early spermatids into full on spermatozoa, which are released into the lumen of the testes for their journey.

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system. Without it, you will just have to memorize the words. Waves of Spermatogenesis occur through the seminiferous tubules. In human males, each cycle of Spermatogenesis takes about 64 days

Sertoli cells are key in spermatogenesis. They

(1) reduce the amount of gamete cytoplasm (sperm should be small and compact for motility), (2) are responsible for the formation of the segments of the spermatid; the head (with the gamete

nucleus and the acrosome , a cap filled with hydrolytic enzymes) , midpiece (where the mitochondria is), and the tail (microtubules key form motility).

(3) induce spermiation, where sertoli cells break cytoplasmic bridges with spermatozoa releasing them into the lumen.

Capacitation is the final step of functional maturation for Spermatozoa. Capacitation is essentially the activation of the sperm. It consists of changes in the acrosome (enzyme cap) to allow penetration of the Zona Pellucida (a glycoprotein coat surrounding the ovum).

Capacitation Capacitation occurs as the spermatozoa move from seminiferous tubules of the male to the Ampulla of the Oviduct in the female. It prepares Spermatozoa for fertilization of the oocyte. Sperm produced in seminiferous tubules are stored in the epididymis (coiled region of vas deferens ). Upon ejaculation, as many as 40 100 million spermatozoa are expelled and mixed with secretions from the Seminal vesicles, prostate, and bulbourethral glands.

Upon expulsion, the sperm move through the vagina, uterus, into fallopian tubes (oviducts), and into the ampulla, where Spermatozoa typically fertilize the ovum in ampulla (expanded region of the fallopian tubes). Sperm in the ampulla retain fertilization viability for 13 days. Capacitation occurs in the female genital tract as sperm contacts secretions from the oviduct. The changes in pH lead to the changes that

activate capacitation.

II. Fertilization: A COMPLEX INTERACTION BETWEEN SPERM AND OOCYTE:

Fertilization is where the Sperm forces way through Cumulus Mass, reaches the Zona Pellucida (glycoprotein coat), binds to a human specific glycoprotein sperm receptor, which induces the release of degradative enzymes from the acrosome, which allows Sperm to penetrate the Zona pellucida.

Mitochondrion

Golgi

Mitochondrion

Acrosome

Nucleus Residual Cytoplasm

Acrosome Nucleus

AcrosomeTail

Head

Neck

Nucleus

MItochondria

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Upon reaching the oocyte, the cell membranes of the sperm and oocyte fuse, stimulating the release of small Cortical Granules (just under oocyte membrane) to release their contents in the space between oocyte membrane and zona pellucida. Material from cortical granules alters Sperm receptors in the zona pellucida, thereby blocking receptor function. Thus,

the zona pellucida becomes impenetrable to sperm preventing Polyspermy . This is a rapid, almost immediate activation once one sperm is in, no others can get in. The zona pellucida is a moat of gasoline. Only when the ferry comes across and guides one sperm over, can that sperm cross (the ferry is the receptor). Once the sperm gets inside, the oocyte lights a match (the cortical granules) and sets the moat on fire (preventing anyone else from crossing).

Fusion of oocyte and sperm cell membranes induces the oocyte to resume Meiosis II, completing Meiosis. This process produces a polar body in the oocyte. The first polar body (made in gametogenesis in the female) completes its second meiotic division. The oocyte is now the definitive oocyte.

Chromosomes of the oocyte and sperm are enclosed in female and male pronuclei. Pronuclei fuse to produce a single diploid (2n) zygote. Within 24 hours after fusion of the pronuclei, the zygote undergoes a rapid series of cell divisions.

Cleavage . These cell divisions are called cleavages because the divisions are not accompanied by cell growth, giving rise to smaller daughter cells. Normally, a cell grows, doubles its DNA, grows again, then splits. In this early embryonic stage, no growth occurs its more important that the cells divide than it is that they grow, and they are already contained in a confined space (the altered zona pellucida aka the

Capacitation an d fertilization

Pronuclei

Male Pronuclei

One sperm made

it, though many try

Fusing Pronuclei

Nucleus undergoing mitosis (denoted by indentation on the top and bottom, separation of chromosomes at center

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fiery moat).

The cells enclosed in the zona pellucida are called blastomeres . These cells then form a ball of cells called the morula . Get ready for name changes and a ton of vocabulary (as if you havent had enough) because keeping track of cells over time is a BEAR.

Compaction. At the 8cell stage, cellcell contacts develop in the outer cells. They become a concentric layer of cells that separates the outer cell mass from the inner cell mass. This pattern continues for most of development.

III. Implantation:

Mechanism of implantation . On days 5 to 6, the embryonic pole of the blastocyst attaches to and begins to erode/penetrate into the uterine mucosa. Penetration of the uterine mucosa is a result of the action of proteolytic enzymes produced by the trophoblast (also called the syncytiotrophoblast). Finger like processes of syncytio trophoblast (outer layer) continue to invade and erode the endometrial epithelium (epithelium is the outer layer, like skin), and the endothelium (the lining of tissue under the

epithelium) of the uterine capillaries, while the rest of the trophoblast is cyto trophoblast.

State of the uterus at the time of implantation: The wall of the uterus has three layers: endometrium, myometrium, and perimetrium. The epithelium covers the three layers. To give you a taste of things to come, all organs are lined by an epithelium; your

Zona Pellucida Barr Bodies

Blastomere Outer Cell mass

Cleavage occurs within the rigid zona pellucida so that multiple cells are formed. Because there is nowhere for the cells to grow, they become progressively smaller (compaction). Eventually, the zygote will give rise to two distinct layers: an inner and outer cell mass

Inner cell mass

Cavity

Syncytiotrophoblast is eating into the uterine epithelium

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skin is an epithelium, the lining of your stomach is an epithelium, the inside of your mouth is an epithelium. Do not get epithelium confused for endo, myo or peri metrium. The endometrium is in the secretory phase, and the uterine glands and arteries have become coiled; the stroma is succulent. Its a good thing you havent had histo or anatomy on this yet, so you have no idea what this means. This

wont be a test question.

The endometrium shows three sub layers: a superficial compact layer , an intermediate spongy layer and a thin basal layer . Upon fertilization, the endometrial glands become very active, secreting mucus and glycogen, and the arteries become tortuous, forming a dense superficial capillary bed. This is the gravid uterus: the endometrium is edematous and pale and ready for the blastocyst.

If the oocyte is not fertilized, the Corpus Luteum involutes and changes toward the menstrual phase. Dont worry about that right now, there will be a lot on menstruation in histology & physiology.

Implantation Process :

Implantation is

supposed

to

occur

on

the

anterior

wall

of

the

uterus ,

but

can

occur

on

any

vascularized mucous membrane the blastocyst falls on. Mucous Membrane means everything inside the female for the most part. If implantation occurs near the internal uterine os ( which is called placenta previa), severe bleeding and other serious problems may result. Ectopic (out of place) implantations do occur, and usually lead to the death of the embryo and often to severe maternal hemorrhaging. Some ectopic pregnancies will go to term (e.g. placenta previa), most will not.

Ectopic sites of implantation include: Abdominal pregnancy implantation in the abdominal cavity, the pouch of Douglas (recto uterine pouch), on a mesentery or the surface of a kidney. These give rise to lithopedians, or stone babies. Tubal pregnancy implantation in the oviduct or Fallopian tube (infundibular/fimbrial), ampullary, isthmic and interstitial regions. Primary ovarian pregnancy implantation on the ovary itself. Placenta previa implantation on the lower uterine segment or on the internal os of the uterus.

Secondary implantation may occur; tubal pregnancies are often expelled and end up as abdominal pregnancies. Simultaneous implantation is a dangerous possibility: a normal intrauterine pregnancy may mask, for a time, the presence of an ectopic one. This can only occur when two oocytes are released and are fertilized separately (as in the case of fertility drug administration).

IV. Early Abortions: An Abortion is any termination of pregnancy before the period of viability has been reached (that is, before 20 weeks of gestation). Early abortions are common events, which often occur before pregnancy

is recognized, and hence go unnoticed, or are mistaken for delayed menstruation. One third to one half of all zygotes never live to implant, and half or more of those that do soon abort.

Almost all abortions during the first three weeks are spontaneous. Chromosomal abnormalities account for 1/2 of spontaneous abortions (nondisjunction during oogenesis is one mechanism). Some Teratogens (agents inducing or favoring congenital malformations) acting in the first two weeks may cause early abortions.

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V. Second Week of Development /Formation of Bilaminar Embryo or Germ Disc: After fertilization, the zygote will undergo cleavage (a series of rapid mitotic divisions). The overall size of the mass of cells increases very little while the number of cells increases (compaction ). The ball of cells is known as a morula .

Blastocyst formation . Spaces form in the morula, dividing the cell mass into two part: the (1)trophoblast (outer cell mass), which will give rise to the fetal component of the placenta, and the (2) inner cell mass, which will give rise to the embryo proper. A cavity forms between the inner and outer cell masses and is filled by fluid. Five to six days following fertilization, the outer cell layer of the blastocyst will differentiate into two layers, an inner cytotrophoblast (cellular trophoblast) and an outer syncytiotrophoblast (syncytium). I want to point out, again, that the trophoblast (the outer cell layer) becomes two layers: the cyto and the syncytio trophoblast. The cytotrophoblast and syncytiotrophoblast will form the fetal component of the placenta.

The inner cell mass, which has not been given a name, divides into two flattened layers of cells, the

epiblast (ectoderm)

and

hypoblast

(endoderm).

This

is

the

bilaminar

embryo

that

was

the

subject

heading for todays lecture.

The prochordal plate . It is the rostral (head) area of tight apposition between the endoderm (hypoblast) and ectoderm (epiblast). We have a music group called Rostral Caudal, and it is what I use to keep the two words straight. Rostral comes first, and the head is more important/higher up, so it comes first. Thus rostral means towards the head, and caudal means towards the anus. The prochordal plate is the site of the future mouth and a key organizer region . It is an example of tissue affinity, an important developmental principle.

The connecting stalk is a bridge of extraembryonic mesoderm from trophoblast to embryo. Ugh what the hell does that mean? Basically its a connection between mom to baby, made from stuff that is not the developing embryo (extra embryonic). Mesoderm is this magical substance that can become just about anything. The connecting stalk is the route of the future umbilical blood vessels .

VI. Second Week of Development (Time table): This is less important. Hill doesnt like questions like when does this happen, but that doesnt mean he cannot ask you. What happens and in which order is

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more important than the day it happens on. Use Dr. Hills MAC BABY software for this portion. You have to know this stuff, but the level of detail and vocabulary is intense after what youve just gone through. Ive put it in here for reference, but use mac baby.

8th day of development: Differentiation of trophoblast into cytotrophoblast & syncytiotrophoblast. Differentiation of the embryoblast (inner cell mass) into epiblast (ectoderm) & hypoblast (endoderm). Formation of amniotic cavity.

9th day of development: 1. Embedment of blastocyst and closure of penetration defect (plug) in the endometrium. Delamination of Heuser's membrane from cytotrophoblast. Formation of the primitive yolk sac [endoderm].

11 12th days of development: Establishment of the uteroplacental circulation: Penetration of syncytiotrophoblast cells into stroma/erosion of endothelium of maternal capillaries (sinusoids) and entrance of maternal blood into

the lacunar

spaces

of

the

trophoblast.

Origin of the extra embryonic mesoderm from the cytotrophoblast. Cavitation of extra embryonic mesoderm and formation of the extraembryonic coelom (chorionic cavity).

Extra embryonic somatopleuric mesoderm (lines cytotrophoblast and amnion) and extra embryonic splanchnopleuric mesoderm (covers yolk sac).

Growth of bilaminar germ disc: spread of endoderm to form Heuser's membrane.

13th day of development: Formation of primary stem villi (a core of cytotrophoblast and outer syncytiotrophoblast.) Involution of primary yolk sac and appearance of secondary or definitive yolk sac. Expansion of extra embryonic coelom/chorionic cavity. Establishment of the chorion: a later stage of the original trophoblastic capsule, to which a lining

of extra embryonic mesoderm has been added. The chorionic plate (extra embryonic mesoderm lining the inside of the cytotrophoblast) and its

connection to the embryo via the connecting stalk. The chorion is a protective and nutritive membrane: it shields the blastocyst within and through

its lining of mesoderm and connecting stalk and offers a route for blood vessels (umbilical vessels) to run to and from between the embryo and the chorionic villi (primitive placenta)

Amniotic cavity begins to form as fluid filled spaces coalesce into one large cavity. Amnioblasts, cells of lining, are derived from ectoderm.

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EmbryoAugust 7th: Trilaminar Embryo


To get ANY idea about what this looks like in 3D you MUST USE Dr Hills Mac Baby. The questions will be from these words, but your understanding will come only from Mac Baby.

I. Formation of the Trilaminar Embryo During the third week, the embryo is developing rapidly, and this development is characterized by the formation of the primitive streak and the three germ layers from the bilaminar disc.

A. Formation of Bilaminar Embryo. After implantation, spaces begin to appear between the inner cell mass, and these spaces will coalesce to form the amniotic cavity. Changes are occurring in the inner cell mass so that it is transformed into the embryonic disc (a flattened circular plate of cells). This disc initially consists of two layers: (1) the epiblast (ectoderm), composed of high columnar cells that are related to the amniotic cavity and (2) the hypoblast (endoderm), which is composed of cuboid cells that lie next to the blastocyst cavity.

B. Gastrulation the process by which the inner cell mass is converted into a trilaminar embryonic disc. Gastrulation begins at the end of the first week/beginning of the 2nd week of development as the hypoblast and epiblast are formed and is completed by the end of the third week. In the third week, a thickened midline band of epiblastic (ectodermal) cells, known as the primitive streak, begins to develop in the caudal aspect of the embryonic disc. The primitive streak forms as a result of the proliferation and piling up of epiblastic cells along the posterior aspect of the embryonic disc (primitive knot, primitive pit).

Primitive groove a depression that forms in the midline of the primitive streak. Epiblastic cells migrate from the periphery to the midline, pile up to form the primitive streak, cells invaginate, and move to the deep aspect of the primitive streak, break loose and migrate rostrally, caudally, and laterally between the two original layers of the bilaminar disc forming a third layer, the intraembryonic mesoderm.

As soon as the primitive streak begins to produce intraembryonic mesoderm, the epiblast and hypoblast are referred to as the ectoderm and endoderm respectively.

Mesodermal cells all of the cells that arise from the primitive streak. These cells are precursors to a variety of cell types that will form connective tissues (bone, cartilage, blood and muscle, etc.).

C. Formation of the Notochord. The notochordal process is a midline cellular cord formed by mesodermal cells, which migrate rostrally from the primitive knot. It will grow rostrally between the ectoderm and endoderm until it reaches the prochordal plate (oropharyngeal membrane). The prochordal plate is a circular area composed of columnar endodermal cells (which are normally cuboid), which are tightly applied to the overlying ectoderm. This will ultimately form the oropharyngeal membrane, the future mouth region. Some mesodermal cells migrate

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laterally and cranially from the primitive streak between the ectoderm and endoderm. These mesodermal cells will continue to migrate laterally and cranially until they reach the margins of the embryonic disc and will join the extraembryonic mesoderm. Some cells of the primitive streak migrate cranially on each side of the notochordal process and around the prochordal plate, where they meet cranially. This area is referred to as the primitive cardiogenic area, the site of the future heart.

The Notochord = a rod of cells which develops from the notochordal process. The notochord is important because it defines the primitive axis of the embryo and gives the embryo some rigidity. As the notochordal process grows cranially, the primitive pit will extend into it, forming the notochordal canal (lumen). The notochordal process is nothing more than a column of cells that extends from the primitive knot to the prochordal plate. As the notochordal process develops, its deeper cells fuse with the underlying endoderm and degenerate. As a result, an opening appears along the floor of the notochordal process and allows the notochordal canal to communicate with the primary yolk sac.

The notochordal process flattens out, forming a grooved plate known as the notochordal plate, which will fold upon itself, beginning at its cranial end, to form a solid column of cells, the notochord. The notochord is a column of cells around which the vertebral column forms. It induces the overlying surface ectoderm to form the neural plate (the primordium of the central nervous system). There are two exceptions to this trilaminar arrangement. They are the oropharyngeal membrane (rostral) and cloacal membrane (caudal), the site of the future anus, which are bilaminar. By the end of the 3rd week, the ectoderm and endoderm are separated by the intraembryonic mesoderm, except at these two sites. Ultimately, the primitive streak degenerates into an insignificant structure in the sacrococcygeal region, which may sometimes persist and give rise to a tumor known as a teratoma .

D. Neurulation. Neurulation is the process by which the neural plate develops, folds, and forms the neural tube. This process begins in the third week and is finished by the end of the fourth week, during which process the embryo is referred to as a neurula.

Neuroectoderm is the ectoderm overlying the notochord, which is induced by the notochord to thicken and give rise to the neural plate. Neuroectoderm will ultimately give rise to the central nervous system. The neural plate first begins to form rostral to the primitive knot and dorsal to the notochord and will extend as far cranially as the

oropharyngeal membrane. The neural plate will invaginate along its central axis, forming the neural groove. Neural folds (elevations) appear on each side of the neural groove and will move towards the midline and fuse with each other to form the neural tube. Keep all of those neurals straight. As the neural tube forms, it loses contact with the overlying surface ectoderm and sinks into the underlying mesoderm.

As the neural tube forms, some of the neuroectodermal cells (which originally lie close to the crest of each neural fold) lose their affinity for other neuroectodermal cells and begin to migrate away from the rest of the

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neuroectodermal cells. These cells are referred to as neural crest cells . Neural crest cells migrate ventrolaterally (out to the side and towards the front) on each side of the neural tube and initially come to lie between the neural tube and the surface ectoderm.

II. Development of Body Form

A. Allometric Growth. The germ layers undergo Allometric growth of the three germ layers. This means that not all germ layers grow at the same rate. The order of the three germ layers from dorsal to ventral are: ectoderm, mesoderm, then endoderm. The endodermal layer forms base for growth of the other two layers.

B. Head and tail folds . In the third week, the trilaminar embryo is a flat disc that is broader rostrally and narrower caudally. The main feature is the primitive streak. As organ systems develop, the embryo changes shape through a process called morphogenesis . Because of rapid growth during this period, exposure to teratogens result in major congenital malformations. The ectodermal and mesodermal layers grow very rapidly and soon overgrow the slow growing endodermal base. This results in a ventral folding of the embryo at the rostral and caudal ends, forming the head and tail folds. The rapid growth of the neural tube also plays a major role in craniocaudal folding of the embryo.

There are two regions, which remain bilaminar (ectoderm and endoderm): the oropharyngeal (rostral) and the cloacal (caudal) membranes. These two regions are relatively stationary (due to lack of endodermal growth) and will form the mouth and the anus.

C. Establishment of foregut By the end of the third week, the notochord induces overlying ectoderm to form neural folds, which will fuse, forming the brain and spinal cord. The most rostral part of the brain (forebrain) proliferates rapidly and overgrows the stationary oropharyngeal membrane, which serves as a fulcrum around which the forebrain rotates ventrally. This folding pulls the more rostral portion of the yolk sac into the embryo to form the foregut. The foregut will take a position between the developing brain (rostral) and the developing heart (caudal). The oropharyngeal membrane separates the foregut from the amniotic cavity, but will rupture at the end of third week allowing the amniotic cavity and gut to communicate.

D. Establishment of cardiogenic area. Early angiogenesis occurs in the extra embryonic mesoderm of the yolk sac and allantois. This results in: (a) Formation of blood cells, and (b) Formation of endothelial lined spaces (primitive blood vessels).

Intra embryonically, angiogenesis occurs just rostral to oropharyngeal membrane in the primitive cardiogenic area. Blood islands (cell clusters that can make blood) form and cavitate, giving rise to primitive blood vessels. Primitive blood vessels coalesce to form two longitudinal heart tubes.

The cardiogenic area is initially rostral to the oropharyngeal membrane, but it rotates 180 o ventrally and caudally (to the front and over the head), under the prospective head region of embryo (during formation of head fold) and now lies caudal to the oropharyngeal membrane.

E. Development of septum transversum. The septum transversum develops from extra embryonic mesoderm just anterior to the primitive cardiogenic region and will rotate 180 o along with the cardiogenic area, but will come to lie caudal to cardiogenic area, under prospective head region. Septum transversum gives rise to the ventral portion of diaphragm. Thats the important part about the septum transversum.

F. Development of the hindgut: Tail fold develops at the caudal end of the embryo shortly after formation of head fold. The caudal part of neural tube overgrows the stationary cloacal membrane, and the whole region rotates 180 o. The caudal portion of the

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yolk sac is incorporated into the embryo as the hindgut.

The cloaca forms as the terminal portion of the hindgut dilates and is separated from the amniotic cavity by the cloacal membrane. The allantois , a small dilation just caudal to the cloaca, has rotated 180 o and will be incorporated into the umbilical cord.

G. Development of lateral body folds: There is also significant lateral growth (sideways) of the embryo, which results in the lateral folding of the embryo. The somatopleure on each side folds down towards the midline, pushing the edges of the embryonic disc ventrally, ultimately forming a cylindrical embryo. The middle portion of the yolk sac is incorporated into the embryo, giving rise to the midgut . The lateral folding of the embryo also results in the medial movement of the two longitudinal heart tubes. These tubes, which will form the heart, were originally located rostral to the oropharyngeal membrane, but now lie caudal to the oropharyngeal membrane. Shortly, the two longitudinal heart tubes will fuse in the midline, forming a single endocardial heart tube.

The establishment of the foregut and hindgut are primarily the result of head and tail fold formation, while the midgut is produced by the lateral folding and will retain its connection with the yolk sac. This connection will rapidly constrict and elongate to form the vitelline duct.

H. Formation of the umbilical cord. The amniotic cavity expands more rapidly than the embryo, and as a result it, overgrows the embryo and chorionic cavity. The amnion envelops the connecting stalk and yolk sac, compressing them to form the primitive umbilical cord. At its distal end, the umbilical cord contains the vitelline duct (yolk stalk) and umbilical vessels. More proximally, it will contain the midgut and allantois.

I. Formation of the intraembryonic coelom. The intraembryonic coelom forms from small isolated spaces in the lateral plate mesoderm, which coalesce forming a single horseshoe shaped cavity that splits the lateral plate mesoderm into two layers: somatic and splanchnic mesoderm. Somatic (parietal) mesoderm is continuous with the extraembryonic mesoderm lining the amnion. Splanchnic (visceral) mesoderm is continuous with the extraembryonic mesoderm lining the yolk sac.

With continued lateral folding of the embryo, the two components of the intraembryonic coelom are brought together on the ventral surface of the embryo, forming a single continuous cavity. The intraembryonic coelom will give rise to the following body cavities: (a) pericardial cavity, which houses the heart, (b) pleural cavities, which house the lungs, (c) peritoneal cavity, which houses the GI organs.

J. The gastrointestinal tract. 1. The GI tract is derived from foregut, midgut and hindgut. 2. Is actually a tube within a tube

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ANATOMY: August 17th Spinal Cord Development

This was a lot of review from both embryo prior to this and from the anatomy lecture on the vertebral column. If youve been following along up to this point, this should have just been a reinforcement of information that you

already know with a few more terms thrown in. The end of this lecture brings up hebbian synapsing and the importance of neural crest cells.

Objective 1: Be able to define Neural Plate, Neural Fold, Neural Ube, Neuropores, Neurulation and the approximate time in human pregnancy this occurs, the neural crest cells and their migration, deriviatives of the

neural crest.

During gastrulation the notochord forms from mesodermal cells called the mesnenchyme. It grows from the primitive pit in the layer of ectoderm, growing rostrally and caudally, extending the pharyngeal and cloiacal membrane. In humans, the notochord is a crucial structure, not for the structure it provides, but for its inductive

nature. In 1, we see the inductive nature of the notochord. In the ectoderm above, the neural groove forms, along the back of the embryo, rostral to caudal. These cells are the future CNS and will form the neural tube . Flanking

the neural groove are two ridges called the neural fold , which will close (as depicted in figure 2) around the top onto itself. It does this in the center of the embryos back and moves rostrally and caudally simultaneously. As

depicted in figure 2 as well, there are neural crest cells that ride the neural fold. As the two sides of ectoderm come together, the neural crest cells will pinch off into mesoderm, allowing for closure of the neural tube. Surface ectoderm destined to become skin also pinches off and seals the nacent nervous system below a protective layer. The red dot in figure 2 is the notochord. Neural Crest cells will eventually become the spinal ganglion and peripheral nervous system while they neural tube will become the central nervous system. Neighbooring mesoderm will form the vertebral column and incorporate the notochord to form the nucleus pulposus of the intervertebral discs. Since we are forming a tube, and tubes have openings at either end (called nuclear pores ) it is critical that these eventually seal, else expose the nervous system to the external environment. Neurulation occurs at about week 3 and takes until the end of week 4 to complete. Keep in mind that body folding is occurring

simultaneously, and all other developmental aspects are occurring.

FOR DISORDER OF CLOSURE OF THE NEURAL TUBE, CALLED SPINA BIFIDA, REFER TO THE VERTEBRAL

LECTURE: ANATOMY AUGUST 17 th VERTEBRAL COLUMN. Eat folic acid = dont get these birth defects

1 2

Neural Groove

Neural

Pore

Neural

Tube

Neural Crest

Neural Crest Neural

Groove

Ectoderm

Future

CNS

Future

PNS

Future Skin

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ANATOMY: August 17th Spinal Cord Development

Neural Crest Failures: Hirschsprungs Disease and Waardenburg

This is a disease caused by the innappropriate formation of the enteric nervous system of the gut. The enteric

nervous system, amongst other things, controls peristalsis (the rythmic contraction and relaxation of smoothe muscle that forces food boluses along the GI tract). While the exact cause of the disease is not known, what is

known is that regions of the GI tract are not innervated by the enteric nervous system which results in a lack or peristalsis, which creates a massive bowel obstruction which is fatal. It is thought to be a problem within the innervation of the gut. GlialDerived Neurotrophic Factor (GDNF) promotes migration of neural crest stem cells to their target. The gene Ret which codes a receptor on the neural crest cells responds to GDNF. If either GDNF or Ret fail, the neural crest cells will not migrate nor form connections where they should. Regions of uninnervated tissue can be surgically removed.

Type I Waardenburg have a white forelock, congential deafness, and different colored eyes. It is caused by a mutation of a regulatory gene expressed by neural crest cells called PAX3

Objective 3: Establishment and Refinement of neuronal connections

(1)

(2)

Connections . During development there are long and short acting messages sent to the developing neuron by the target cell. While it is

not well understood, chemoattraction and chemorepulsion act over long distances, and continue their signaling even if the developing

landscape changes (cutting a developing sensory neuron will still innervate its target, even though, in time, it crosses different structures

from its normal development). What was said in lecture was that Nerve Growth Factor (NGF) and Glial Derived Neurotophic Factor (GDNF) are

some of the important factors. What is key is that more neurons develop than are found in the adult. Many neurons die as a result of programmed cell death. Survival is activity dependent and is promoted by neuotrophic factors. Hebbian Synapsing states that cells that fire together wire together (thus persist and survive) while cells out of sync, lose their link (and suffer programmed cell death). Figure 2 demonstrates this in a cartoon, where the spikes of 1 and 2 are

concurrent and 3 is not, 1 and 2 persist, 3 dies. Cells without synapses, die as well. NGF is the survival factor, it is produced by tissues innervated by the sympathetic nervous system and small sensory neurons. In fact, it is possible to have peripheral nerve regeneration in the presence of NGF. The cell knows a connection has been

made or lost through two mechanisms. Fast axonal transport transports growth factors and proteins both in and out (transmission of NGF to soma, for example). Slow axonal transport is structural carrying not just messages, but building blocks. It is about 2mm/day and happens to be the rate of nerve rengeration.

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EmbryoAugust 18th Development of Musculoskeletal System

| T 1 F o r D u m m i e s , M a k i n g F i r s t Y e a r a L i t t l e E a s i e r

I. Development of the Skeletal System: The skeletal system develops from the mesodermal germ layer, which appears during the third week of development. Mesodermal cells will give rise to a loosely organized tissue known as mesenchyme (embryonic connective tissue). Mesenchymal cells are pluripotent , meaning they have the ability to differentiate down several different pathways. One cell can become many different cell types.

Neural crest cells in the head region can differentiate into mesenchymal cells and migrate into the branchial arches to form a cartilage bar and will ultimately participate in the formation of the bones of the face.

The embryonic mesoderm can be divided into three basic regions, proceeding from medial to lateral: 1) Paraxial mesoderm thickening of mesoderm adjacent to the developing notochordal process, forming a longitudinal column of cells. This column of mesoderm is continuous with the intermediate and lateral mesoderm. In the third week, the paraxial mesoderm undergoes segmentation into somites (paired cuboid bodies). The first pair of somites develop just caudal to the cranial end of the notochord, and new pairs of somites appear in sequence from cranial to caudal. During the somite period of development about 38 pairs of somites develop. Somites will give rise to most of the axial skeleton (vertebral column and the ribs).

Paraxial Mesoderm = Somites = Axial Skeleton.

2) Intermediate mesoderm is located between the paraxial mesoderm and the lateral mesoderm and has very little to do with the formation of the skeletal system, but is more concerned with the formation of the urogenital system, including gonads, ducts, and accessory glands.

3) Lateral plate mesoderm will split into two segments as the intraembryonic coelom forms. The two layers are the mesoderm of the somatopleure, which is continuous with the extraembryonic mesoderm lining the amnion and the mesoderm of the splanchnopleure, which is continuous with the

extraembryonic mesoderm covering the yolk sac.

Visualization of the relationship of the lateral, intermediate and

paraxial mesoderm in the early embryo. Pay close attention to coelomic spaces and the neural groove

A little later in development. The neural tube has formed, the

coelomic spaces have opened and the lateral mesoderm has been split into somatic and splanchnic mesoderm.

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Somites appear as pairs of bead like elevations along the dorsolateral surface of the embryo. Shortly after somites form, their ventral and medial walls lose their organization and break up into two masses of cells. The more ventro medial mass is referred to as a sclerotome (larger) and the dorsolateral mass is the dermomyotome (smaller).The sclerotomic mass migrates between the notochord, the neural tube and the primitive gut and will finally surround the notochord.

Other mesodermal cells also migrate along with the sclerotome and take up a position around the notochord. These mesenchymal cells eventually become surrounded by sclerotomic cells known as the perichordal tube (they form a tube around the tube). Each sclerotome, as it surrounds the notochord, consists of loosely arranged cells. At the head, there is a cranially loose perichordal disc and at the back end, packed cells caudally dense perichordal disc. With the formation of the perichordal discs, the notochord begins to show segmentation, enlarging within the dense perichordal discs and narrowing within the loose perichordal disc.

Each dense perichordal disc and the enlarged portion of the notochord within it will form the intervertebral disc. Cells of the dense perichordal disc above join the cells of the loose perichordal disc below to form the body of each arch. Therefore, each centrum is believed to develop from two adjacent sclerotomes and is thus an intersegmental structure.

The portion of the notochord surrounded by the vertebral body will degenerate, but the region of the notochord outside the vertebra will expand to form the nucleus pulposus (the gelatinous central portion of the intervertebral disc). The annulus fibrosus is derived from the dense perichordal disc and is

This picture has a lot in it, but focus only on the important stuff. This demonstrates the development of a somite into a scleratome, which then migrates around the neural tube. The notochord is the spinal cord, the sclerotome becomes the bone

around the

spinal

cord.

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composed of fibers arranged in a circular manner around the nucleus pulposus. These two components constitute the intervertebral disc. Sometimes remnants of the notochord persist in some part of the axial skeleton and give rise to a chordoma (base of the skull or in the lumbosacral region).

The arch of the vertebra is formed by mesenchymal cells from the dense caudal part of the sclerotome that surround the neural tube. Cells in the central aspect of the developing arch are derived from the loose disc and will degenerate to form a vertebral foramen.

Development of the ribs. Rib blastema (pre rib structures) arise from lateral projections of the dense perichordal disc (fig. 15 6A). One arises on each side of the intervertebral disc. As the rib primordium grows laterally, it arches dorsally and caudally (towards the back and the head) and will ultimately contact the transverse process of the vertebral arch.

Thus, the ultimate derivatives of the sclerotome are: centrum of the vertebra, neural arch, rib, and the annulus fibrosus.

Chondrification of the vertebrae and ribs (6th week). Chondrification means turning into cartilage. This process has to happen first, where chondrocytes (cells that make cartilage) develop. Once they are there, ossification turning into bone can take place. Two centers of chondrification develop within the centrum of the vertebra. At the same time, each half of the vertebral arch and each rib primordia develop a chondrification center.

The nerve migrates through the loosely

packed top and densely packed bottom. The regions of cells between growing nerves fuse to form the vertebrae. The myotome develops into muscles, which are then innervated by the nerves.

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Ossification of the vertebrae and ribs. Primary ossification centers begin to form during the 8 th week of development at the same sites that the chondrification centers developed. Initially, two ossification centers develop (one ventral and one dorsal), in each centrum, but fuse to form one central center called the primary ossification center . A primary ossification center also develops in each vertebral (neural) arch, and ossification proceeds

dorsally into

the

lamina,

ventrally

into

the

pedicle,

laterally

into

the

transverse

process

and

into

the

articular processes.

Development of the sternum. The sternum begins as a pair of mesenchymal bands that develop in the ventrolateral body wall. These plates of mesenchyme chondrify to form two sternal plates. The plates will fuse in a craniocaudal direction and the cranial 6 or 7 costal cartilages will attach to them. Picture a zipper, zipping from the top down, then the growing ribs inserting themselves into the one zipped plate.

Ossification centers appear prior to birth with the exception of the xiphoid process, which ossifies sometime during childhood.

Secondary ossification centers do not begin to appear until the onset of puberty and continue to appear until approximately 20 years of age. Each typical vertebra has 5 secondary ossification centers: (1) tip of the spinal process, (2) the end of each

transverse process, (3) two annular (rim) epiphyses, (4) one cephalic, and (5) one caudal

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II. Development of the muscular system: Skeletal Muscle The muscular system develops from the mesodermal germ layer . Muscle development is first indicated

by the

elongation

of

the

nuclei

and

cell

bodies

of

mesenchymal

cells

(derivatives

of

somites)

to

form

myoblasts . Mesenchyme can become lots of things. When it becomes myoblasts, its on its way to the muscular system. We call that differentiation. Somite Myotome Myoblast myotube.

Somitic Epithelium = Somites Myotomes. Myotomes have myogenic progenitor cells in them that then become myoblasts. Myoblasts form myotubes. Myotubes then form myofibers.

Somites differentiate into masses of cells known as myotomes . Cells of the myotome split off and become elongated and spindle shaped (myoblast ). Myoblasts differentiate and fuse with each other forming a long, multinucleated cylindrical structures known as myotubes . Muscles will eventually be formed by the continued fusion of myotubes.

Myofilaments (actin/myosin) begin to form shortly after the fusion of myoblasts. Myofilaments form myofibrils, which become evident in the cytoplasm of the myotubes by the end of the third month, forming cross striations. Muscle cells are referred to as muscle fibers because they develop from these long myotubes and have an elongated narrow form that resembles fibers. Not all striated muscle fibers develop prior to birth; some fibers will develop during the first year following birth.

Somites and Somitomeres Many skeletal muscles are derived from either somites or somitomeres. A somitomeres is a structure found in the cephalic and occipital regions that resembles immature somites. These are of branchiomeric origin and are referred to as branchiomeres. Somites appear along side of the developing spinal cord in the various body regions (see above).

Myotomes develop from somites, and each myotome is composed of two divisions, a small dorsal, epaxial division and a larger ventral, hypaxial division. SmallDorsal Epaxial; Larger Ventral Hypaxial. Each spinal nerve divides and sends a branch to each division, the dorsal primary ramus to the epaxial division and the ventral primary ramus to the hypaxial division. Each division of a myotome forms a specific group of muscles.

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Epimeres (myoblasts from the epaxial division; meres means cells; epi means come from epaxial division) form the deep dorsal trunk muscles (extensors of the back and vertebral column and extensors of the lumbar region) and are supplied by dorsal primary rami of the corresponding spinal nerve. Hypomeres (myoblasts from the hypaxial division; meres means cells; hypo means from hypaxial division) form all of the remaining muscles of the trunk and some limb muscles and are supplied by ventral primary rami of spinal nerves.

The hypomeres give rise to both the lateral and ventral flexor musculature. The ventral musculature splits into 3 separate layers, which can be identified in the thorax as the external intercostal, the internal intercostal, and the innermost intercostals or the transverse thoracis muscle. In the abdominal wall, these 3 layers consist of the external oblique, the internal oblique and the transverse abdominus

muscle. The intercostals regain their segmented character due to the presence of the ribs. Most muscles however, are formed by myoblasts that have migrated and have fused with other myoblasts to form sheets of muscles.

Branchiomeres (myoblasts from the branchial arches, which develop into the face, something you have not covered yet; meres means cells; branchio means from branchial arches) form the muscles of mastication and facial expression, as well as certain pharyngeal and laryngeal muscles; these muscles become innervated by the branchial arch nerves: The trigeminal (V), facial (VII), glossopharyngeal

This image shows the relationship of the myotome and the

dermatome within the dermomyotome first, then of the

epimere and hypomere second. The large Image behind the two

close ups shows what the epimere and the hypomere will become. Link these developmental stages and locations with your Superficial and Deep Back from anatomy to determine innervation.

This is a cross section of the abdomen (like a CT scan) showing the fates of the epimere and the hypomeres, including which muscles they will

become and what they are innervated by. This specifically shows the abdominal muscles and where they come from.

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(IX) and vagal (X). This is in Hills notes, but you will not get to cranial nerves, nor facial development until the end of anatomy. There was no good image of this.

Most of the limb musculature develops from migrating somatic cells (epimeric or hypomeric cells), but some develops in situ from the mesenchyme surrounding the developing bones. Some migration from

epimeres and

hypomeres

does

occur.

Origin and development of smooth muscle: Smooth muscle of the GI tract is derived from the splanchnic mesoderm surrounding the endoderm of the primitive gut and its outgrowths (liver, gallbladder, pancreas). Some smooth muscle, specifically that which is found in the walls of many blood vessels and lymphatic channels, is derived from somatic mesoderm . Still some other smooth muscles, like that of the of the iris (sphincter and dilator pupillae), as well as the myoepithelial cells of the mammary glands, are thought to be derived from mesenchymal cells of neural crest (ectoderm) origin.

GI = Splanchinic Mesoderm, Blood Vessels = Somatic Mesoderm, Iris = Neural Crest Ectoderm,

The train of events in myoblast development is somewhat different from that seen in skeletal muscle development, and no fusion of adjoining myoblasts occurs. Smooth muscles are NOT multinucleated fibers (as you will learn in detail in Histo/physio), so there is no fusion of cells.

Origin and development of cardiac muscle: Cardiac muscle originates from the splanchnic mesoderm surrounding the early endocardial heart tube (myoepicardial mantle). The cardiogenic myoblasts form the myocardium. There is no fusion of myoblasts as is seen in the development of skeletal muscle (like smooth muscle, cardiac muscle is not multinucleated). The individual myoblasts differentiate and grow, adding to their complement of myofibrils, and eventually adhere to one another at junctional interfaces, which ultimately become the complex structures known as intercalated discs . Atypical cardiac muscle fibers that make up the

Purkinje fibers of the heart's conducting system will form late in the embryonic period.

III. Limb Development UPPER LIMB appears on day 24 as small bulges on the lateral body wall at C5C8 level, while the LOWER LIMB appears at L3L5 several days after the development of the upper limb

Limb Musculature and Development Cellular and Molecular Aspects: The Limb bud consists of a mesenchymal core covered over by an ectodermal cap. The Limb bud is induced to form by adjacent somites. The distal margin of the ectodermal cap thickens to form the Apical Ectodermal Ridge (AER). The AER is induced to form by the mesodermal core. It then acts back on the mesoderm. Mesenchyme adjacent to AER consists of undifferentiated cells that are induced by AER to differentiate into the mesenchymal model, blood vessels, cartilage, and bone models. So the mesoderm tells the ectoderm to become the AER, then the AER tells the mesoderm to become a limb.

The limbs come from the somatopleuric lateral plate mesoderm, which migrate outwards. At the same time, myotomes migrate and invade the mesoderm. The mesoderm will be the bone, the dermatome the skin, and the myotome the muscle of the developing limb. Most of this section was sped through, and Hill wanted to focus more on the molecular basis rather than the development of the limb itself.

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Molecular basis of pattern formation The spatial organization of differentiated cells and tissues accounts for the morphogenesis of the organs and body as a whole. Zone of polarizing Activity (ZPA) produces a morphogen gradient that can be interpreted by cells in limb bud. Because concentration will be greater closer to the ZPA and less farther away, the gradation allows for control of gene expression and thus development.

Early studies suggested that Retinoic Acid was the morphogen produced by cells in the ZPA. The concentration of Retinoic Acid is 2.5 times higher in ZPA than other sites. There is a concentration gradient of RA from apical to distal. We now believe FGF8 stimulates SHH in ZPA. Yes, it is called Sonic Hedge Hog. No, they were not Sega fans, but rather the spines on the backs of organisms of SHHknockouts resembled a hedgehog.

This next section is a dip into biochemistry, where we explore nuclear receptors. This is kept intentionally brief. Cells of limb buds contain Retinoic Acid Receptors (RAR). RARs are steroid receptors (opposed to plasma membrane surface receptors) and act as nuclear transcription factors (acting and changing DNA directly) that activate or repress the transcription of specific genes. To target that DNA, there must be steroid response elements, or, in this case retinoic acid receptor response elements, RAREs. So when Retinoic acid is produced, it binds to its receptor, which then binds DNA, turning on or turning off gene expression.

So important is this concept that there are a few exercises one can do. If you take the ZPA from one embryo and put it on a developing embryo, you get another limb. If you place a bead full of retinoic acid instead of the new ZPA, you get another limb. The actual experiment was done with fingers and digit number, shown on the next page. But the gist is that the ZPA, via retinoic acid, is the inducer of segmentation.

Myotome migrates and

invades mesoderm, generating the bud

Over the course of weeks, the

limb bud extends,

differentiates, and

gives

rise

to a hand plate, then to individual digits.

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FGF8 from AER is also a steroid hormone, inducing the expression of homeobox genes (HOX genes). These are master gene that regulate the expression of other genes by producing transcription factors. Hox 4 genes activated in a cranio caudal sequence and are key in proximal distal differentiation. Retinoic Acid induces FGF9 and FGF2 expression which in turn regulate the expression of SHH gene

and HOX 4 and 7 genescritical for limb patterning.

D. CONGENITAL ANAMALIES OF THE LIMB: There are three categories of limb defects: (1.) reduction defects in which part of a limb (meromelia ) or and entire limb (amelia ) is missing. (2.) duplication defects in which there are more than you should have (polydactyly is the presence of extra digits and is the most common example). (3.) Dysplasia malformation of the limb include syndactyly (fusion of the digits), and gigantism ( excessive growth of the digits)

ZPA taken from another embryo or a bead with

retinoic acid produce the same result

embryo block 1

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