INTRODUCTION TO EMBRYOLOGY

Assoc Prof Dr E.Elif GÜZEL

Definition of Embryology • The study of the developmental process from a single cell to a

baby in 9 months. • In other words, investigations of the molecular, cellular and

structural factors contributing to the formation of an organism.

• Development does not stop at birth!! • How does it start? • Zygote (totipotent cell) Human • Transformation mechanisms include:

– cell division, – cell migration, – apoptosis, – differentiation, – growth, – cell rearrangement

Human Development

Clinical Importance • Understanding embryology is essential for creating health

care strategies; 1. Prenatal diagnosis and surgical treatments 2. Therapeutic procedures for infertility 3. Mechanisms to prevent birth defects

improved birth outcomes

postnatal long-term effects

prenatal experiences effects cognitive capacity and postnatal health

IMPOTANT FOR MOST PHYSICIANS

Improvements in prenatal and reproductive health is significant for

• Embryogenesis (organogenesis);

– Establishment of the organ primordia from a single cell

– The first 8 weeks of human development

• Fetal period;

– From 9th week to birth

– Differentiation and growth

– Fetus gains weight

• Trimester;

– 1/3 of the normal length of pregnancy

• Teratology;

– Study of the embryological causes for birth defects

• Genetic

• Environmental

• Spermatozoon= Sperm • According to the anatomical position, the position of the

organs are described using some terms: – Anterior/ventral – Posterior/dorsal – Superior/ cranial (or rostral) – Inferior/caudal

Descriptive Terms in Embryology

Molecular Regulation of Embryogenesis

• Progress in the field of molecular biology enhanced our understanding of normal and abnormal development

• 23,000 genes…..150,000 proteins

Chromatin

• Chromatin: a complex of DNA and histone proteins

• Nucleosome: the basic structural unit of chromatin

• Nucleosomes keep the DNA tightly coiled, such that it cannot be transcribed….heterochromatin

• DNA must be uncoiled to be transcribed…. euchromatin

Gene Transcription

**Transcription Factors

• Protein that binds to specific DNA sequences, and control the transcription of genetic information from DNA to mRNA.

• Depending on the transcription factor, the transcription of the adjacent gene is either activated or inhibited.

Regulation of Gene Expression

**DNA Methylation

• Methylation of cytosine bases in the promoter regions of genes inhibits transcription of those genes.

• Some genes are silenced by this mechanism

– Muscle cells make muscle proteins not blood proteins

**Alternative Splicing

• Why different cells by using the same gene produce different proteins?? A single gene may give rise to several proteins

• By removing different introns from pre-mRNA

• Splicing isoforms

Post-translational Modifications • Activation of some proteins depends on….

– Combination with other proteins – Phosphorylation – Cleavage

Induction and Organ Formation

• How does organ formation occur???

One group of cells or tissues causes another set of cells or tissues to change their fate

INDUCTION

Organs are formed by interactions between cells and tissues

Inducer-Cell Signaling-Responder

Inductive Interactions Between Epithelial and Mesenchymal Cells

• Epithelial cells join together to form tubes or sheets • Mesenchymal cells are fibroblastic in appearance and dispersed in

extracellular matrix • Although an initial signal from inducer to responder starts the inductive

event, crosstalk between two tissues or cell types is essential for differentiation to continue

Examples of Epithelial-Mesenchymal Interactions

• Gut endoderm and surrounding mesenchyme…. gut derived organs (liver, pancreas)

• Development of the kidney

Cell Signaling

• Essential for induction • Established by signaling proteins (ligand) • Receptor

– Spans the cell membrane • Extracellular domain (ligand binding region) • Transmembrane domain • Cytoplasmic domain

• Action??? – Activating directly – Blocking the activity of an inhibitor of a pathway

(inhibiting an inhibitor)

Typical Signal Transduction Pathway Process 1. Ligand binds its receptor….. 2. Conformational change occurs in the receptor…. 3. Cytoplasmic region gains an enzymatic activity (mostly kinase)…. 4. Phosphorylation of some cytoplasmic proteins…. 5. Activation of a transcription factor…. 6. Activation or inhibition of genes.

Types of Signal Transduction Pathways

• Paracrine Signaling; proteins synthesized by one cell diffuse short distances to interact with other cells

• Juxtacrine Signaling; does not involve diffusable proteins

Paracrine Signaling

• Diffusable proteins responsible for the paracrine signaling are called paracrine factors or growth and differentiation factors (GDFs).

• Uses typical signal transduction pathway process.

Juxtacrine Signaling 1. A protein on one cell surface interacts with a receptor on

an adjacent cell uses typical signal transduction pathway process Notch signaling (neuronal and blood vessel differentiation,

somite segmentation)

2. Ligands in the extracellular matrix interact with their receptors on neighboring cells (cells attach to or migrate on these ligands) Epithelial cells attach to laminin of basal lamina Fibronectin for cell migration Receptors are called integrins

3. Gap junctions

Paracrine Signaling Factors (GDFs)

• Regulate development and differentiation of organ systems

• Grouped into 4 families; – Fibroblast growth factor – WNT – Hedgehog – Transforming growth factor-β (TGF-β )

Fibroblast Growth Factors (FGFs) • Originally named because they stimulate the growth of fibroblasts in

culture • app. 25 different genes….hundreds of proteins • Receptor tyrosine kinases (FGFRs) • Important for;

– angiogenesis – axon growth – mesoderm differentiation

• e.g. FGF8 is important for development of the limbs and part of the brain

Hedgehog Proteins

• There are 3 hedgehog genes; – Desert – Indian – Sonic hedgehog

• Sonic Hedgehog is important in – Limb patterning – Neural tube induction or patterning – Somite differentiation – Gut regionalization

• Action on the receptor is inhibiting an inhibitor

WNT Proteins

• Involved in regulating….

– limb patterning

– midbrain development

– somite differentiation

– urogenital differentiation

TGF-β Superfamily

• More than 30 members – TGF-βs

• Important for extracellular matrix formation

• Important for epithelial branching that occurs in the lung, kidney and salivary gland development

– Bone morphogenetic proteins (BMPs) • Induces bone formation

• Regulates cell division, apoptosis, cell migration

– Activin familiy

– Müllerian inhibiting factor

Other Paracrine Signaling Molecules

• Two neurotransmitters important for embryological development

• Seratonin (5HT) – Cell proliferation – Cell migration – Establishing laterality – Gastrulation – Heart development

• Norepinephrine – Apoptosis in interdigital spaces

References

1. The Developing Human: Clinically Oriented Embryology by Keith L. Moore, T. V. N. Persaud and Mark G. Torchia (2013). 9th ed. Elsevier Saunders, Philadelphia. ISBN: 978-0-8089-2444-9

2. Langman’s Medical Embryology by T.W. Sadler (2012). 12th ed. Lippincott Williams & Wilkins, Philadelphia. ISBN: 978-1-4511-4461-1