Development of the nervous system
The construction of the nervous system is one of the most complex processes in embryology. Development of the nervous system, or neural development, refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. In vertebrates, it begins with the formation of the neural tube from the ectoderm via neurulation. This tube then differentiates into the brain and spinal cord through regionalization and patterning by morphogen gradients. Subsequent stages include neurogenesis neuronal migration, axon guidance, synaptogenesis, and extensive activity-dependent refinement to produce functional neural circuits. This field of neural development draws on both neuroscience and developmental biology to describe and provide insight into the cellular and molecular mechanisms by which complex nervous systems develop, from nematodes and fruit flies to mammals.
Recent advances in genomics and imaging technologies, such as single-cell sequencing and live-cell microscopy, have refined our understanding of neural development at molecular and cellular levels. Techniques such as single-cell RNA sequencing allow researchers to profile gene expression in individual neural progenitors and neurons, revealing previously unknown cellular diversity during development. 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, and in humans other disorders such as Rett syndrome, Down syndrome and intellectual disability.
Vertebrate brain development
The vertebrate central nervous system is derived from the ectoderm—the outermost germ layer of the embryo. A part of the dorsal ectoderm becomes specified to neural ectoderm – neuroectoderm that forms the neural plate along the dorsal side of the embryo. In humans, neural tube closure is typically complete by the end of the fourth week of gestation. Failure of closure can result in neural tube defects such as spina bifida or anencephaly. This is a part of the early patterning of the embryo that also establishes an anterior-posterior axis. The neural plate is the source of the majority of neurons and glial cells of the CNS. The neural groove forms along the long axis of the neural plate, and the neural plate folds to give rise to the neural tube. This process is known as neurulation. When the tube is closed at both ends it is filled with embryonic cerebrospinal fluid. As the embryo develops, the anterior part of the neural tube expands and forms three primary brain vesicles, which become the forebrain, midbrain, and hindbrain. These simple, early vesicles enlarge and further divide into the telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon. The CSF-filled central chamber is continuous from the telencephalon to the central canal of the spinal cord, and constitutes the developing ventricular system of the CNS. Embryonic cerebrospinal fluid differs from that formed in later developmental stages, and from adult CSF; it influences the behavior of neural precursors. Because the neural tube gives rise to the brain and spinal cord any mutations at this stage in development can lead to fatal deformities like anencephaly or lifelong disabilities like spina bifida. During this time, the walls of the neural tube contain neural stem cells, which drive brain growth as they divide many times. Gradually some of the cells stop dividing and differentiate into neurons and glial cells, which are the main cellular components of the CNS. The newly generated 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 to communicate with other neurons via synapses. Synaptic communication between neurons leads to the establishment of functional neural circuits that mediate sensory and motor processing, and underlie behavior.Image:development of nervous system.svg|thumbnail|750px|center|Flowchart of human brain development
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. 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 groove. Beginning in the future neck region, the neural folds of this groove close to create the neural tube. The formation of the neural tube from the ectoderm is called neurulation. The ventral part of the neural tube is called the basal plate; the dorsal part is called the alar plate. The hollow interior is called the neural canal, and the open ends of the neural tube, called the neuropores, close off.
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, suggesting that neural differentiation is the default fate of ectodermal cells. In explant cultures the same cells differentiate into epidermis. This is due to the action of BMP4 that induces ectodermal cultures to differentiate into epidermis. During neural induction, noggin and chordin are produced by the dorsal mesoderm and diffuse into the overlying ectoderm to inhibit the activity of BMP4. This inhibition of BMP4 causes the cells to differentiate into neural cells. Inhibition of TGF-β and BMP signaling can efficiently induce neural tissue from pluripotent stem cells.
Regionalization
In a later stage of development the superior part of the neural tube flexes at the level of the future midbrain—the mesencephalon, at the mesencephalic flexure or cephalic flexure. Above the mesencephalon is the prosencephalon and beneath it is the rhombencephalon.The alar plate of the prosencephalon expands to form the telencephalon which gives rise to the cerebral hemispheres, whilst its basal plate becomes the diencephalon. The optical vesicle forms at the basal plate of the prosencephalon.
Patterning
In chordates, dorsal ectoderm forms all neural tissue and the nervous system. Patterning occurs due to specific environmental conditions - different concentrations of signaling moleculesDorsoventral 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.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 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.
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.