Divyan Bavan
Introduction
The central nervous system (CNS) is one of the most intricate networks within the body. It consists primarily of two structures: the brain and spinal cord. These structures themselves are highly complex, consisting of multiple subregions. The complex patterns observed are a result of highly coordinated and intricate development. Several stages have been defined for the development of the CNS, each with distinct pathways involved. As with other developmental processes, this is the result of various morphogen gradients and cell migrations. When these processes fail, however, several abnormalities of the CNS can transpire. Thus, placing these diseases in the context of developmental stages—neural induction, neurulation, neural tube patterning, neurogenesis, and further brain development—can aid in understanding and treating them.
Split 1: Neural Induction and Neurulation
The first step for the development of the CNS is neural induction. This process starts from the trilaminar embryo, the product of gastrulation. At this point in development, the embryo has three layers: the endoderm, mesoderm, and ectoderm. The latter is what eventually differentiates into the nervous system and epidermis. To form the CNS, ectodermal cells must be differentiated specifically into neural cells. This is the task of neural induction (Schoenwolf et al., 2021).
On day 18 of development, the ectoderm thickens and forms a thick plate of neuroepithelial cells. This process occurs due to signalling from the notochord and axial mesoderm, collectively termed the organizer. This centre releases several factors—noggin, chordin, follistatin, cerebrus, and more—which are bone morphogenetic protein antagonists. These factors block BMP signalling by binding to the protein, inhibiting its effect. This leads to the differentiation of the ectoderm into neural tissue; BMP in the absence of antagonists leads to the epidermal tissue. Like the rest of the embryo, the neural plate also has axes. The cranial and caudal ends of the plate eventually form the brain and spinal cord, respectively. This is driven by elongation of the caudal neuroepithelium. The result is a tapered caudal end and a broad cranial end, foreshadowing the final structure of the CNS. This process is driven by a retinoic acid gradient, which leads to the generation of the caudal neural plate. Thus, even at the earliest stages of development, the structure of the CNS is already being planned out (Schoenwolf et al., 2021).
Neural induction is followed by neurulation: the formation of the neural tube. Once the neural plate is formed, it must fold and fuse to form a tube. The first step of this process is the shaping of the neural plate. As sonic hedgehog protein (Shh) is released from the notochord, neural folds start to form. These folds are raised dorsally around a pivot point: the median hinge point. This forms the neural groove. After the formation of the neural groove, the neural folds must fuse together. This is mediated by the dorsolateral hinge points, which direct the folds to move towards each other. Finally, the folds are raised and fuse together. This process starts at the cervical region, progressing in both directions to close the neural tube. While this is considered the end of neurulation, another process—termed secondary neurulation—is also necessary to complete formation of the neural tube. This occurs at the end of the caudal neural tube, where the tail bud forms the sacral, coccygeal, and tail regions of the spinal cord (Schoenwolf et al., 2021).
Defects caused from issues with neural induction and neurulation have been well documented. One famous example is spina bifida. This abnormality occurs when there is improper closure of the caudal neural tube. Although this condition is not fatal—as opposed to anencephaly, which is caused by improper closure of the cranial neural tube—it does lead to problems with posture. In more severe cases, this can cause paralysis. To prevent these issues, folate has been shown to reduce spina bifida occurrence (Karsonovich et al., 2025; Schoenwolf et al., 2021).
Step 2: Neural Tube Patterning
After the neural tube is formed, it must be further patterned to develop specific structures. At the cranial end, three divisions start to form: the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain). These structures are the primary brain vesicles and form the three main divisions of the brain. During the fifth week, the prosencephalon divides into the telencephalon and diencephalon; the rhombencephalon divides into the metencephalon and myelencephalon. Along with the mesencephalon, these structures form the secondary brain vesicles. These areas go on to form the different tissues of the brain. Furthermore, the neural canal is still present within each of these areas. In each of the primary vesicles, it forms a primitive ventricle. These will go on to form the four ventricles of the brain. Thus, even in the early stages of development, the overall structure of the CNS is already being built out (Schoenwolf et al., 2021).
At the caudal end of the neural tube, the spinal cord is also being patterned. This occurs through morphogen gradients, leading to differentiation of the spinal cord columns. In the ventral neural tube, neural tissue is influenced by the floor plate. This signalling centre is induced by the notochord, and releases Shh. The result of this is the differentiation of the tissue into motor neurons. On the other hand, the dorsal neural tube is under the influence of the roof plate. This area secretes BMPs and Wnts, causing differentiation of the tissue into sensory interneurons. Thus, the major divisions of the spinal cord are also being developed at this point in development (Schoenwolf et al., 2021).
When these signalling molecules are disrupted, several defects can form. For example, holoprosencephaly is caused by improper separation of the cerebral hemispheres. This is due to defects in Shh, causing interrupted dorsoventral patterning. The result of this is face abnormalities, cognitive impairments, and more (Ramakrishnan et al., 2024).
Step 3: Development of the Brain
Although the spinal cord has complexity, it is the brain that holds most of the intricacy within the CNS. The brain must develop both its structure and circuitry. The former lays the foundation and is developed early on, whereas the latter develops into childhood.
After formation of the primary brain vesicles, the neural tube bends and forms three flexures: the cephalic, cervical, and pontine flexures. These flexures organize the orientation of the brain and establish its axes. After this, the five secondary brain vesicles are shaped to form the various structures of the brain. For example, the telencephalon expands rapidly to form the forebrain structures—cerebral cortex, basal ganglia, and others. The myelencephalon forms the medulla, and resembles the dorsoventral patterning of the spinal cord (Schoenwolf et al., 2021).
This expansion is driven by neurogenesis: the differentiation of stem cells into neurons. Neurogenesis starts in the ventricular zone. This layer of neuroepithelial cells lines the neural canal. At the beginning of this process, these cells—which eventually are called radial glia cells—divide symmetrically, producing two progenitor cells. This expands the stem cell pool. Soon, however, these progenitors start dividing asymmetrically: producing one progenitor and one neuron. This maintains the population of stem cells while producing neurons at the same time (Schoenwolf et al., 2021).
Once neurons are produced, they can migrate either radially or tangentially. The ones that migrate radially form the excitatory cortical neurons. The development of the cortex takes place in layers, with the deeper layers being formed first followed by the superficial layers. Neurons migrate through the radial glial scaffolding. To form the GABAergic interneurons, however, neurons must move tangentially. These neurons are formed from the ganglionic eminences of the ventral telencephalon (Schoenwolf et al., 2021).
The last steps of development include neuronal death and synaptogenesis. Not all neurons which are formed will end up as part of the developed brain. By competing for neurotrophic factors, only neurons which are important will survive. This increases efficiency. Finally, neurons rapidly form and prune synapses with each other to form cortical circuits. These circuits are not static and continue to be adjusted even beyond adulthood.
Defects can occur at several points throughout the development of the brain. For example, improper balance of symmetric and asymmetric stem cell division can reduce the number of neurons formed. This leads to microcephaly. The causes for microcephaly are hypoxia in utero, alcohol intake by the mother, and centrosomal genetic defects. Neuronal migration can also be affected in defects. This is found in lissencephaly, where neurons fail to migrate to the surface of the brain. The result of this is the absence of folds and a “smooth brain”. This leads to significant developmental delays and epilepsy (Schoenwolf et al., 2021; Kattuoa et al., 2023).
Conclusion
It is evident that there are many stages for the development of the CNS. The process starts with neural induction from the ectoderm. This leads to the differentiation of neuroepithelial cells. These cells eventually form folds around the median hinge point, induced by the presence of Shh. These folds bend and fuse together, forming the neural tube. At this point, the CNS is already starting to take form. The broad cranial end of the tube forms three primary brain vesicles. The tapered caudal end forms the spinal cord, patterned dorsally and ventrally by BMPs and Shh, respectively. This forms the sensory dorsal interneurons and the ventral motor neurons. Going back to the brain, the primary vesicles eventually form the secondary brain vesicles. These vesicles form the structures of the brain, while the neural canal is shaped to form the four ventricles. It is at this point where neurons are formed through neurogenesis. After differentiation, they migrate to form the cortical layers and GABAergic interneurons. Finally, synapses are formed between neurons to form its circuitry. Due to the complexity of this process, several defects can occur from issues in development. These include spina bifida, microcephaly, lissencephaly and more. Therefore, continuing to develop our understanding of neurodevelopment is critical for being able to treat these diseases.
Works Cited
Brea, Cristina M., and Sunil Munakomi. “Spina Bifida.” PubMed, StatPearls Publishing, 13 Aug. 2023, www.ncbi.nlm.nih.gov/books/NBK559265/.
Kattuoa, Mohammad l, and Joe M Das. “Lissencephaly.” PubMed, StatPearls Publishing, 2022, www.ncbi.nlm.nih.gov/books/NBK560766/.
Ramakrishnan, Sharanya, and Vikas Gupta. “Holoprosencephaly.” PubMed, StatPearls Publishing, 2022, www.ncbi.nlm.nih.gov/books/NBK560861/.
Schoenwolf, Gary C, et al. Larsen’s Human Embryology. Philadelphia, Pa, Elsevier, 2021.