Neural developmentFrom Wikipedia, the free encyclopedia

This article is about neural development in all types of animals, including humans. For information specific to thehuman nervous system, see Neural development in humans.

Neural development refers to the processes that generate, shape, and reshape the nervous system, from the earlieststages of embryogenesis to the final years of life. The study of neural development aims to describe the cellular basisof brain development and to address the underlying mechanisms. The field draws on both neuroscience anddevelopmental biology to provide insight into the cellular and molecular mechanisms by which complex nervoussystems develop. Defects in neural development can lead to cognitive and motor impairment, as well as neurologicaldisorders such as autism, Rett syndrome, and intellectual disability.[1]

Contents1 Overview of brain development2 Aspects of neural development3 Neural induction4 Regionalization5 Patterning of the nervous system

5.1 Dorsoventral axis5.2 Rostrocaudal (Anteroposterior) axis

6 Neuronal migration6.1 Radial migration6.2 Tangential migration6.3 Axophilic migration6.4 Other modes of migration

7 Neurotrophic factors8 Synapse formation

8.1 Neuromuscular junction8.2 CNS synapses8.3 Activity dependent mechanisms in the assembly of neural circuits

9 Synapse elimination10 See also11 References12 Notes13 External links

Overview of brain developmentThe nervous system is derived from the ectoderm—the outermost tissue layer—of the embryo. In the third week ofdevelopment the neuroectoderm appears and forms the neural plate along the dorsal side of the embryo. This neuralplate is the source of the majority of neurons and glial cells in the mature human. A groove forms in the neural plateand, by week four of development, the neural plate wraps in on itself to make a hollow neural tube.[2] Because thisneural tube later gives rise to the brain and spinal cord any mutations at this stage in development can lead to lethaldeformities like anencephaly or lifelong disabilities like spina bifida. Later development yields areas known as the twolateral ventricles and the third ventricle. The telencephalon, which eventually encompasses the two lateral ventricles,

gives rise to areas of the brain known as the Basal Ganglia and the Limbic System.[3] Gradually some of the cells stopdividing and differentiate into neurons and glial cells, which are the main cellular components of the brain. The newlygenerated neurons migrate to different parts of the developing brain to self-organize into different brain structures.Once the neurons have reached their regional positions, they extend axons and dendrites, which allow them tocommunicate with other neurons via synapses. Synaptic communication between neurons leads to the establishmentof functional neural circuits that mediate sensory and motor processing, and underlie behavior. The human brain doesmost of its development within the first 20 years of life.

Flowchart of human brain development.

Aspects of neural developmentSome landmarks of neural development include the birth and differentiation of neurons from stem cell precursors, themigration of immature neurons from their birthplaces in the embryo to their final positions, outgrowth of axons anddendrites from neurons, guidance of the motile growth cone through the embryo towards postsynaptic partners, thegeneration of synapses between these axons and their postsynaptic partners, and finally the lifelong changes insynapses, which are thought to underlie learning and memory.

Typically, these neurodevelopmental processes can be broadly divided into two classes: activity-independentmechanisms and activity-dependent mechanisms. Activity-independent mechanisms are generally believed to occur ashardwired processes determined by genetic programs played out within individual neurons. These includedifferentiation, migration and axon guidance to their initial target areas. These processes are thought of as beingindependent of neural activity and sensory experience. Once axons reach their target areas, activity-dependentmechanisms come into play. Although synapse formation is an activity-independent event, modification of synapsesand synapse elimination requires neural activity.

Developmental neuroscience uses a variety of animal models including mice Mus musculus, the fruit fly Drosophilamelanogaster, the zebrafish Danio rerio, Xenopus laevis tadpoles and the worm Caenorhabditis elegans, amongothers.

Neural induction

During early embryonic development the ectoderm becomes specified to give rise to the epidermis (skin) and theneural plate. The conversion of undifferentiated ectoderm to neuro-ectoderm requires signals from the mesoderm. Atthe onset of gastrulation presumptive mesodermal cells move through the dorsal blastopore lip and form a layer inbetween the endoderm and the ectoderm. These mesodermal cells that migrate along the dorsal midline give rise to astructure called the notochord. Ectodermal cells overlying the notochord develop into the neural plate in response to adiffusible signal produced by the notochord. The remainder of the ectoderm gives rise to the epidermis (skin). Theability of the mesoderm to convert the overlying ectoderm into neural tissue is called neural induction.

The neural plate folds outwards during the third week of gestation to form the neural groove. Beginning in the futureneck region, the neural folds of this groove close to create the neural tube. The formation of the neural tube from theectoderm is called neurulation. The ventral part of the neural tube is called the basal plate; the dorsal part is called thealar plate. The hollow interior is called the neural canal. By the end of the fourth week of gestation, the open ends ofthe neural tube, called the neuropores, close off.[4]

A transplanted blastopore lip can convert ectoderm into neural tissue and is said to have an inductive effect. Neuralinducers are molecules that can induce the expression of neural genes in ectoderm explants without inducingmesodermal genes as well. Neural induction is often studied in xenopus embryos since they have a simple bodypattern and there are good markers to distinguish between neural and non-neural tissue. Examples of neural inducersare the molecules noggin and chordin.

When embryonic ectodermal cells are cultured at low density in the absence of mesodermal cells they undergo neuraldifferentiation (express neural genes), suggesting that neural differentiation is the default fate of ectodermal cells. Inexplant cultures (which allow direct cell-cell interactions) the same cells differentiate into epidermis. This is due to theaction of BMP4 (a TGF-β family protein) that induces ectodermal cultures to differentiate into epidermis. Duringneural induction, noggin and chordin are produced by the dorsal mesoderm (notochord) and diffuse into the overlyingectoderm to inhibit the activity of BMP4. This inhibition of BMP4 causes the cells to differentiate into neural cells.Inhibition of TGF-β and BMP (bone morphogenetic protein) signaling can efficiently induce neural tissue from humanpluripotent stem cells,[5] a model of early human development.

RegionalizationLate in the fourth week, the superior part of the neural tube flexes at the level of the future midbrain—themesencephalon. Above the mesencephalon is the prosencephalon (future forebrain) and beneath it is therhombencephalon (future hindbrain).

The optical vesicle (which eventually become the optic nerve, retina and iris) forms at the basal plate of theprosencephalon. The alar plate of the prosencephalon expands to form the cerebral hemispheres (the telencephalon)whilst its basal plate becomes the diencephalon. Finally, the optic vesicle grows to form an optic outgrowth.

Patterning of the nervous systemIn chordates, dorsal ectoderm forms all neural tissue and the nervous system. Patterning occurs due to specificenvironmental conditions - different concentrations of signaling molecules

Dorsoventral axis

The ventral half of the neural plate is controlled by the notochord, which acts as the 'organiser'. The dorsal half iscontrolled by the ectoderm plate, which flanks either side of the neural plate.[6]

Ectoderm follows a default pathway to become neural tissue. Evidence for this comes from single, cultured cells ofectoderm, which go on to form neural tissue. This is postulated to be because of a lack of BMPs, which are blocked bythe organiser. The organiser may produce molecules such as follistatin, noggin and chordin that inhibit BMPs.

The ventral neural tube is patterned by Sonic Hedgehog (Shh) from the notochord, which acts as the inducing tissue.Notochord-derived Shh signals to the floor plate, and induces Shh expression in the floor plate. Floor plate-derivedShh subsequently signals to other cells in the neural tube, and is essential for proper specification of ventral neuronprogenitor domains. Loss of Shh from the notochord and/or floor plate prevents proper specification of theseprogenitor domains. Shh binds Patched1, relieving Patched-mediated inhibition of Smoothened, leading to activationof Gli family of transcription factors (Gli1, Gli2, and Gli3) transcription factors.

In this context Shh acts as a morphogen - it induces cell differentiation dependent on its concentration. At lowconcentrations it forms ventral interneurones, at higher concentrations it induces motor neuron development, and athighest concentrations it induces floor plate differentiation. Failure of Shh-modulated differentiation causesholoprosencephaly.

The dorsal neural tube is patterned by BMPs from the epidermal ectoderm flanking the neural plate. These inducesensory interneurones by activating Sr/Thr kinases and altering SMAD transcription factor levels.

Rostrocaudal (Anteroposterior) axis

Signals that control anteroposterior neural development include FGF and retinoic acid, which act in the hindbrain andspinal cord.[7] The hindbrain, for example, is patterned by Hox genes, which are expressed in overlapping domainsalong the anteroposterior axis under the control of retinoic acid. The 3' genes in the Hox cluster are induced byretinoic acid in the hindbrain, whereas the 5' Hox genes are not induced by retinoic acid and are expressed moreposteriorly in the spinal cord. Hoxb-1 is expressed in rhombomere 4 and gives rise to the facial nerve. Without thisHoxb-1 expression, a nerve similar to the trigeminal nerve arises.

Neuronal migrationNeuronal migration is the method by which neurons travel from their origin or birthplace to their final position in thebrain. There are several ways they can do this, e.g. by radial migration or tangential migration. This time lapse(http://www.nature.com/neuro/journal/v4/n2/extref/nn0201-143-S1.mpg) displays sequences of radial migration (alsoknown as glial guidance) and somal translocation.[8]

Radial migration

Neuronal precursor cells proliferate in the ventricular zone of the developing neocortex. The first postmitotic cells tomigrate from the preplate, which are destined to become Cajal-Retzius cells and subplate neurons. These cells do soby somal translocation. Neurons migrating with this mode of locomotion are bipolar and attach the leading edge of theprocess to the pia. The soma is then transported to the pial surface by nucleokinesis, a process by which a microtubule"cage" around the nucleus elongates and contracts in association with the centrosome to guide the nucleus to its finaldestination.[9] Radial glia, whose fibers serve as a scaffolding for migrating cells, can itself divide[10] or translocate tothe cortical plate and differentiate either into astrocytes or neurons.[11] Somal translocation can occur at any timeduring development.[8]

Corticogenesis: younger neuronsmigrate past older ones using radialglia as a scaffolding. Cajal-Retziuscells (red) release reelin (orange).

Tangential migration of interneuronsfrom ganglionic eminence.

Subsequent waves of neurons split the preplate by migrating along radial glialfibres to form the cortical plate. Each wave of migrating cells travel past theirpredecessors forming layers in an inside-out manner, meaning that theyoungest neurons are the closest to the surface.[12][13] It is estimated that glialguided migration represents 90% of migrating neurons in human and about75% in rodents.[14]

Tangential migration

Most interneurons migrate tangentially through multiple modes of migration toreach their appropriate location in the cortex. An example of tangentialmigration is the movement of interneurons from the ganglionic eminence tothe cerebral cortex. One example of ongoing tangential migration in a matureorganism, observed in some animals, is the rostral migratory streamconnecting subventricular zone and olfactory bulb.

Axophilic migration

Many neurons migrating along the anterior-posterior axis of the body useexisting axon tracts to migrate along; this is called axophilic migration. Anexample of this mode of migration is in GnRH-expressing neurons, whichmake a long journey from their birthplace in the nose, through the forebrain,and into the hypothalamus.[15] Many of the mechanisms of this migration havebeen worked out, starting with the extracellular guidance cues[16] that triggerintracellular signaling. These intracellular signals, such as calcium signaling,lead to actin [17] and microtubule[18] cytoskeletal dynamics, which producecellular forces that interact with the extracellular environment through celladhesion proteins [19] to cause the movement of these cells.

Other modes of migration

There is also a method of neuronal migration called multipolarmigration.[20][21] This is seen in multipolar cells, which are abundantlypresent in the cortical intermediate zone. They do not resemble the cellsmigrating by locomotion or somal translocation. Instead these multipolar cellsexpress neuronal markers and extend multiple thin processes in variousdirections independently of the radial glial fibers.[20]

Neurotrophic factorsThe survival of neurons is regulated by survival factors, called trophic factors.The neurotrophic hypothesis was formulated by Victor Hamburger and Rita Levi Montalcini based on studies of thedeveloping nervous system. Victor Hamburger discovered that implanting an extra limb in the developing chick led toan increase in the number of spinal motor neurons. Initially he thought that the extra limb was inducing proliferationof motor neurons, but he and his colleagues later showed that there was a great deal of motor neuron death during

normal development, and the extra limb prevented this cell death. According to the neurotrophic hypothesis, growingaxons compete for limiting amounts of target-derived trophic factors and axons that fail to receive sufficient trophicsupport die by apoptosis. It is now clear that factors produced by a number of sources contribute to neuronal survival.

Nerve Growth Factor (NGF): Rita Levi Montalcini and Stanley Cohen purified the first trophic factor, NerveGrowth Factor (NGF), for which they received the Nobel Prize. There are three NGF-related trophic factors:BDNF, NT3, and NT4, which regulate survival of various neuronal populations. The Trk proteins act asreceptors for NGF and related factors. Trk is a receptor tyrosine kinase. Trk dimerization and phosphorylationleads to activation of various intracellular signaling pathways including the MAP kinase, Akt, and PKCpathways.CNTF: Ciliary neurotrophic factor is another protein that acts as a survival factor for motor neurons. CNTF actsvia a receptor complex that includes CNTFRα, GP130, and LIFRβ. Activation of the receptor leads tophosphorylation and recruitment of the JAK kinase, which in turn phosphorylates LIFRβ. LIFRβ acts as adocking site for the STAT transcription factors. JAK kinase phosphorylates STAT proteins, which dissociatefrom the receptor and translocate to the nucleus to regulate gene expression.GDNF: Glial derived neurotrophic factor is a member of the TGFb family of proteins, and is a potent trophicfactor for striatal neurons. The functional receptor is a heterodimer, composed of type 1 and type 2 receptors.Activation of the type 1 receptor leads to phosphorylation of Smad proteins, which translocate to the nucleus toactivate gene expression.

Synapse formation

Neuromuscular junction

Main article: Neuromuscular junction

Much of our understanding of synapse formation comes from studies at the neuromuscular junction. The transmitter atthis synapse is acetylcholine. The acetylcholine receptor (AchR) is present at the surface of muscle cells beforesynapse formation. The arrival of the nerve induces clustering of the receptors at the synapse. McMahan and Sanesshowed that the synaptogenic signal is concentrated at the basal lamina. They also showed that the synaptogenicsignal is produced by the nerve, and they identified the factor as Agrin. Agrin induces clustering of AchRs on themuscle surface and synapse formation is disrupted in agrin knockout mice. Agrin transduces the signal via MuSKreceptor to rapsyn. Fischbach and colleagues showed that receptor subunits are selectively transcribed from nucleinext to the synaptic site. This is mediated by neuregulins.

In the mature synapse each muscle fiber is innervated by one motor neuron. However, during development many ofthe fibers are innervated by multiple axons. Lichtman and colleagues have studied the process of synapses elimination.This is an activity-dependent event. Partial blockage of the receptor leads to retraction of corresponding presynapticterminals.

CNS synapses

Agrin appears not to be a central mediator of CNS synapse formation and there is active interest in identifying signalsthat mediate CNS synaptogenesis. Neurons in culture develop synapses that are similar to those that form in vivo,suggesting that synaptogenic signals can function properly in vitro. CNS synaptogenesis studies have focused mainlyon glutamatergic synapses. Imaging experiments show that dendrites are highly dynamic during development andoften initiate contact with axons. This is followed by recruitment of postsynaptic proteins to the site of contact.Stephen Smith and colleagues have shown that contact initiated by dendritic filopodia can develop into synapses.

Induction of synapse formation by glial factors: Barres and colleagues made the observation that factors in glialconditioned media induce synapse formation in retinal ganglion cell cultures. Synapse formation in the CNS iscorrelated with astrocyte differentiation suggesting that astrocytes might provide a synaptogenic factor. The identity ofthe astrocytic factors is not yet known.

Neuroligins and SynCAM as synaptogenic signals: Sudhof, Serafini, Scheiffele and colleagues have shown thatneuroligins and SynCAM can act as factors that induce presynaptic differentiation. Neuroligins are concentrated at thepostsynaptic site and act via neurexins concentrated in the presynaptic axons. SynCAM is a cell adhesion moleculethat is present in both pre- and post-synaptic membranes.

Activity dependent mechanisms in the assembly of neural circuits

The processes of neuronal migration, differentiation and axon guidance are generally believed to be activity-independent mechanisms and rely on hard-wired genetic programs in the neurons themselves. New research findingshowever have implicated a role for activity-dependent mechanisms in mediating some aspects of the aforementionedprocesses such as the rate of neuronal migration,[22] aspects of neuronal differentiation[23] and axon pathfinding.[24]

Activity-dependent mechanisms influence neural circuit development and are crucial for laying out early connectivitymaps and the continued refinement of synapses which occurs during development.[25] There are two distinct types ofneural activity we observe in developing circuits -early spontaneous activity and sensory-evoked activity. Spontaneousactivity occurs early during neural circuit development even when sensory input is absent and is observed in manysystems such as the developing visual system,[26][27]auditory system,[28][29] motorsystem,[30]hippocampus,[31]cerebellum[32] and neocortex.[33]

Experimental techniques such as direct electrophysiological recording, fluorescence imaging using calcium indicatorsand optogenetic techniques have shed light on the nature and function of these early bursts of activity.[34][35] Theyhave distinct spatial and temporal patterns during development[36] and their ablation during development has beenknown to result in deficits in network refinement in the visual system.[37] In the immature retina, waves ofspontaneous action potentials arise from the retinal ganglion cells and sweep across the retinal surface in the first fewpostnatal weeks.[38] These waves are mediated by neurotransmitter acetylcholine in the initial phase and later on byglutamate.[39] They are thought to instruct the formation of two sensory maps- the retinotopic map and eye-specificsegregation.[40] Retinotopic map refinement occurs in downstream visual targets in the brain-the superior colliculus(SC) and dorsal lateral geniculate nucleus (LGN).[41] Pharmacological disruption and mouse models lacking the β2subunit of the nicotinic acetylcholine receptor has shown that the lack of spontaneous activity leads to marked defectsin retinotopy and eye-specific segregation.[40]

In the developing auditory system, developing cochlea generate bursts of activity which spreads across the inner haircells and spiral ganglion neurons which relay auditory information to the brain.[42] ATP release from supporting cellstriggers action potentials in inner hair cells.[43] In the auditory system, spontaneous activity is thought to be involvedin tonotopic map formation by segregating cochlear neuron axons tuned to high and low frequencies.[42] In the motorsystem, periodic bursts of spontaneous activity are driven by excitatory GABA and glutamate during the early stagesand by acetylcholine and glutamate at later stages.[44] In the developing zebrafish spinal cord, early spontaneousactivity is required for the formation of increasingly synchronous alternating bursts between ipsilateral andcontralateral regions of the spinal cord and for the integration of new cells into the circuit.[45] In the cortex, earlywaves of activity have been observed in the cerebellum and cortical slices.[46] Once sensory stimulus becomes

available, final fine-tuning of sensory-coding maps and circuit refinement begins to rely more and more on sensory-evoked activity as demonstrated by classic experiments about the effects of sensory deprivation during criticalperiods.[46]

Synapse eliminationMain article: Synaptic pruning

Several motorneurons compete for each neuromuscular junction, but only one survives until adulthood. Competitionin vitro has been shown to involve a limited neurotrophic substance that is released, or that neural activity infersadvantage to strong post-synaptic connections by giving resistance to a toxin also released upon nerve stimulation. Invivo, it is suggested that muscle fibres select the strongest neuron through a retrograde signal.

See alsoNeural development in humansAxon guidancePioneer neuronNeural DarwinismNeurodevelopmental disorderPre- and perinatal psychologyBrain development timelinesMalleable intelligenceHuman brain development timelineMouse brain development timelineMacaque brain development timelineRole of cell adhesions in neural development

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Notes

External linksNeural Development (http://www.neuraldevelopment.com/) (peer-reviewed open access journal).Translating Neurodevelopmental Time Across Mammalian Species (http://www.translatingtime.net/)

Retrieved from "https://en.wikipedia.org/w/index.php?title=Neural_development&oldid=682391002"

Categories: Developmental biology Embryology of nervous system Developmental neuroscience

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