Development of the nervous system

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Neural development
)
This article is about neural development in all types of animals, including humans. For information specific to the human nervous system, see Development of the nervous system in humans. For formation and stabilization of synapses during development, see Synaptic stabilization.
"Developmental Neuroscience" redirects here. For the journal, see
Developmental Neuroscience (journal)
.
"Neural Development" redirects here. For the journal, see
Neural Development (journal)
.
This article is part of a series on the
Development of organ systems

The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the

mammals
.

Defects in neural development can lead to malformations such as holoprosencephaly, and a wide variety of neurological disorders including limb paresis and paralysis, balance and vision disorders, and seizures,[1] and in humans other disorders such as Rett syndrome, Down syndrome and intellectual disability.[2]

Overview of vertebrate brain development

Diagram of the vertebrate nervous system
Further information: Development of the nervous system in humans

The

synapses. Synaptic communication between neurons leads to the establishment of functional neural circuits that mediate sensory and motor processing, and underlie behavior.[12]

Flowchart of human brain development

Aspects

Some landmarks of neural development include the birth and

migration of immature neurons from their birthplaces in the embryo to their final positions, outgrowth of axons and dendrites from neurons, guidance of the motile growth cone through the embryo towards postsynaptic partners, the generation of synapses between these axons and their postsynaptic partners, and finally the lifelong changes
in synapses, which are thought to underlie learning and memory.

Typically, these neurodevelopmental processes can be broadly divided into two classes: activity-independent mechanisms and

migration and axon guidance to their initial target areas. These processes are thought of as being independent of neural activity and sensory experience. Once axons
reach their target areas, activity-dependent mechanisms come into play. Although synapse formation is an activity-independent event, modification of synapses and synapse elimination requires neural activity.

Developmental neuroscience uses a variety of

Xenopus laevis, and the roundworm Caenorhabditis elegans
.

gray matter). Rather than showing the actual myelin, the MRI picks up on the myelin water fraction, a measure of myelin content. Multicomponent relaxometry (MCR) allow visualization and quantification of myelin content. MCR is also useful for tracking white matter maturation, which plays an important role in cognitive development. It has been discovered that in infancy, myelination occurs in a caudal–cranial, posterior-to-anterior pattern. Because there is little evidence of a relationship between myelination and cortical thickness, it was revealed that cortical thickness is independent of white matter. This allows various aspects of the brain to grow simultaneously, leading to a more fully developed brain.[13]

Neural induction

During early

embryonic development of the vertebrate, the dorsal ectoderm becomes specified to give rise to the epidermis and the nervous system; a part of the dorsal ectoderm becomes specified to neural ectoderm to form the neural plate which gives rise to the nervous system.[3][14] The conversion of undifferentiated ectoderm to neuroectoderm requires signals from the mesoderm. At the onset of gastrulation presumptive mesodermal cells move through the dorsal blastopore lip and form a layer of mesoderm in between the endoderm and the ectoderm. Mesodermal cells migrate along the dorsal midline to give rise to the notochord that develops into the vertebral column
. Neuroectoderm overlying the notochord develops into the neural plate in response to a diffusible signal produced by the notochord. The remainder of the ectoderm gives rise to the epidermis. The ability of the mesoderm to convert the overlying ectoderm into neural tissue is called neural induction.

In the early embryo, the neural plate folds outwards to form the

neural canal, and the open ends of the neural tube, called the neuropores, close off.[15]

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

When embryonic ectodermal cells are cultured at low density in the absence of mesodermal cells they undergo neural differentiation (express neural genes), suggesting that neural differentiation is the default fate of ectodermal cells. In

pluripotent stem cells.[16]

Regionalization

In a later stage of development the superior part of the neural tube flexes at the level of the future midbrain—the

rhombencephalon
(future hindbrain).

The alar plate of the prosencephalon expands to form the

optical vesicle
(which eventually become the optic nerve, retina and iris) forms at the basal plate of the prosencephalon.

Patterning of the nervous system

In

chordates, dorsal ectoderm forms all neural tissue and the nervous system. Patterning
occurs due to specific environmental 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 is controlled by the ectoderm plate, which flanks either side of the neural plate.[17]

Ectoderm follows a default pathway to become neural tissue. Evidence for this comes from single, cultured cells of ectoderm, which go on to form neural tissue. This is postulated to be because of a lack of BMPs, which are blocked by the 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-derived Shh subsequently signals to other cells in the neural tube, and is essential for proper specification of ventral neuron progenitor domains. Loss of Shh from the notochord and/or floor plate prevents proper specification of these progenitor domains. Shh binds Patched1, relieving Patched-mediated inhibition of Smoothened, leading to activation of the Gli family of transcription factors (GLI1, GLI2, and GLI3
).

In this context Shh acts as a morphogen - it induces cell differentiation dependent on its concentration. At low concentrations it forms ventral interneurons, at higher concentrations it induces motor neuron development, and at highest concentrations it induces floor plate differentiation. Failure of Shh-modulated differentiation causes holoprosencephaly.

The dorsal neural tube is patterned by BMPs from the epidermal ectoderm flanking the neural plate. These induce sensory interneurons by activating

Sr/Thr kinases and altering SMAD
transcription factor levels.

Rostrocaudal (Anteroposterior) axis

Signals that control anteroposterior neural development include

Hox genes, which are expressed in overlapping domains along the anteroposterior axis under the control of retinoic acid. The 3′ (3 prime end) genes in the Hox cluster are induced by retinoic acid in the hindbrain, whereas the 5′ (5 prime end) Hox genes are not induced by retinoic acid and are expressed more posteriorly in the spinal cord. Hoxb-1 is expressed in rhombomere 4 and gives rise to the facial nerve. Without this Hoxb-1 expression, a nerve similar to the trigeminal nerve
arises.

Neurogenesis

progenitor cells. Neurons are 'post-mitotic', meaning that they will never divide again for the lifetime of the organism.[12]

5-hydroxymethylcytosine) and enzymes of the DNA base excision repair (BER) pathway.[19]

Neuronal migration

radial glia as a scaffolding. Cajal–Retzius cells (red) release reelin
(orange).

Neuronal

migration is the method by which neurons travel from their origin or birthplace to their final position in the brain. There are several ways they can do this, e.g. by radial migration or tangential migration. Sequences of radial migration (also known as glial guidance) and somal translocation have been captured by time-lapse microscopy.[21]

Tangential migration of interneurons from ganglionic eminence

Radial migration

Neuronal precursor cells proliferate in the

microtubule "cage" around the nucleus elongates and contracts in association with the centrosome to guide the nucleus to its final destination.[22] Radial glial cells, whose fibers serve as a scaffolding for migrating cells and a means of radial communication mediated by calcium dynamic activity,[23][24] act as the main excitatory neuronal stem cell of the cerebral cortex[25][26] or translocate to the cortical plate and differentiate either into astrocytes or neurons.[27] Somal translocation can occur at any time during development.[21]

Subsequent waves of neurons split the preplate by migrating along

radial glial fibres to form the cortical plate. Each wave of migrating cells travel past their predecessors forming layers in an inside-out manner, meaning that the youngest neurons are the closest to the surface.[28][29] It is estimated that glial guided migration represents 90% of migrating neurons in human and about 75% in rodents.[30]

Tangential migration

Most interneurons migrate tangentially through multiple modes of migration to reach their appropriate location in the cortex. An example of tangential migration is the movement of interneurons from the ganglionic eminence to the cerebral cortex. One example of ongoing tangential migration in a mature organism, observed in some animals, is the rostral migratory stream connecting subventricular zone and olfactory bulb.

Axophilic migration

Many neurons migrating along the anterior-posterior axis of the body use existing

cell adhesion proteins[35]
to cause the movement of these cells.

Multipolar migration

There is also a method of neuronal migration called multipolar migration.

cortical intermediate zone. They do not resemble the cells migrating by locomotion or somal translocation. Instead these multipolar cells express neuronal markers and extend multiple thin processes in various directions independently of the radial glial fibers.[36]

Neurotrophic factors

The 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 the developing nervous system. Victor Hamburger discovered that implanting an extra limb in the developing chick led to an increase in the number of spinal motor neurons. Initially he thought that the extra limb was inducing proliferation of 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, growing axons compete for limiting amounts of target-derived trophic factors and axons that fail to receive sufficient trophic support 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, Nerve Growth 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 as receptors for NGF and related factors. Trk is a receptor tyrosine kinase. Trk dimerization and phosphorylation leads to activation of various intracellular signaling pathways including the MAP kinase, Akt, and PKC pathways.
  • CNTF: Ciliary neurotrophic factor is another protein that acts as a survival factor for motor neurons. CNTF acts via a receptor complex that includes CNTFRα, GP130, and LIFRβ. Activation of the receptor leads to phosphorylation and recruitment of the JAK kinase, which in turn phosphorylates
    LIFR
    β. LIFRβ acts as a docking site for the STAT transcription factors. JAK kinase phosphorylates STAT proteins, which dissociate from 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 trophic factor 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 to activate 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 at this synapse is acetylcholine. The acetylcholine receptor (AchR) is present at the surface of muscle cells before synapse formation. The arrival of the nerve induces clustering of the receptors at the synapse. McMahan and Sanes showed that the synaptogenic signal is concentrated at the

rapsyn
. Fischbach and colleagues showed that receptor subunits are selectively transcribed from nuclei next 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 of the fibers are innervated by multiple axons. Lichtman and colleagues have studied the process of synapses elimination.[38] This is an activity-dependent event. Partial blockage of the receptor leads to retraction of corresponding presynaptic terminals. Later they used a connectomic approach, i.e., tracing out all the connections between motor neurons and muscle fibers, to characterize developmental synapse elimination on the level of a full circuit. Analysis confirmed the massive rewiring, 10-fold decrease in the number of synapses, that takes place as axons prune their motor units but add more synaptic areas at the NMJs with which they remain in contact.[39]

CNS synapses

Agrin appears not to be a central mediator of CNS synapse formation and there is active interest in identifying signals that 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 mainly on glutamatergic synapses. Imaging experiments show that dendrites are highly dynamic during development and often 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 glial conditioned media induce synapse formation in retinal ganglion cell cultures. Synapse formation in the CNS is correlated with astrocyte differentiation suggesting that astrocytes might provide a synaptogenic factor. The identity of the astrocytic factors is not yet known.

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

Activity dependent mechanisms in the assembly of neural circuits

Further information: Activity-dependent plasticity

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. Research findings however have implicated a role for activity-dependent mechanisms in mediating some aspects of these processes such as the rate of neuronal migration,[40] aspects of neuronal differentiation[41] and axon pathfinding.[42] Activity-dependent mechanisms influence neural circuit development and are crucial for laying out early connectivity maps and the continued refinement of synapses which occurs during development.[43] There are two distinct types of neural activity we observe in developing circuits -early spontaneous activity and sensory-evoked activity. Spontaneous activity occurs early during neural circuit development even when sensory input is absent and is observed in many systems such as the developing visual system,[44][45] auditory system,[46][47] motor system,[48] hippocampus,[49] cerebellum[50] and neocortex.[51]

Experimental techniques such as direct electrophysiological recording, fluorescence imaging using calcium indicators and optogenetic techniques have shed light on the nature and function of these early bursts of activity.

retinotopic map and eye-specific segregation.[58] Retinotopic map refinement occurs in downstream visual targets in the brain-the superior colliculus (SC) and dorsal lateral geniculate nucleus (LGN).[59] Pharmacological disruption and mouse models lacking the β2 subunit of the nicotinic acetylcholine receptor has shown that the lack of spontaneous activity leads to marked defects in retinotopy and eye-specific segregation.[58]

Recent studies confirm that microglia, the resident immune cell of the brain, establish direct contacts with the cell bodies of developing neurons, and through these connections, regulate neurogenesis, migration, integration and the formation of neuronal networks in an activity-dependent manner.[60]

In the developing

critical periods.[65]

Contemporary diffusion-weighted

MRI techniques may also uncover the macroscopic process of axonal development. The connectome can be constructed from diffusion MRI data: the vertices of the graph correspond to anatomically labelled gray matter areas, and two such vertices, say u and v, are connected by an edge if the tractography phase of the data processing finds an axonal fiber that connects the two areas, corresponding to u and v.

Consensus Connectome Dynamics

Numerous braingraphs, computed from the Human Connectome Project can be downloaded from the http://braingraph.org site. The Consensus Connectome Dynamics (CCD) is a remarkable phenomenon that was discovered by continuously decreasing the minimum confidence-parameter at the graphical interface of the Budapest Reference Connectome Server.[66][67] The Budapest Reference Connectome Server (http://connectome.pitgroup.org

) depicts the cerebral connections of n=418 subjects with a frequency-parameter k: For any k=1,2,...,n one can view the graph of the edges that are present in at least k connectomes. If parameter k is decreased one-by-one from k=n through k=1 then more and more edges appear in the graph, since the inclusion condition is relaxed. The surprising observation is that the appearance of the edges is far from random: it resembles a growing, complex structure, like a tree or a shrub (visualized on the animation on the left).

It is hypothesized in

development of the human brain
: the earliest developing connections (axonal fibers) are common at most of the subjects, and the subsequently developing connections have larger and larger variance, because their variances are accumulated in the process of axonal development.

Synapse elimination

Main article: Synaptic pruning

Several motorneurons compete for each neuromuscular junction, but only one survives until adulthood.[38] Competition in vitro has been shown to involve a limited neurotrophic substance that is released, or that neural activity infers advantage to strong post-synaptic connections by giving resistance to a toxin also released upon nerve stimulation. In vivo, it is suggested that muscle fibres select the strongest neuron through a retrograde signal or that activity-dependent synapse elimination mechanisms determine the identity of the "winning" axon at a motor endplate.[39]

Mapping

Brain mapping can show how an animal's brain changes throughout its lifetime. As of 2021, scientists mapped and compared the whole brains of eight C. elegans worms across their development on the neuronal level[69][70] and the complete wiring of a single mammalian muscle from birth to adulthood.[39]

Adult neurogenesis

Main article: Adult neurogenesis

Neurogenesis also occurs in specific parts of the adult brain.

See also

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External links

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Development of the nervous system
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