Development of the Nervous System

Neural development, also referred to as neurodevelopment, encompasses the processes by which the nervous system is generated, organised, and remodelled from the earliest stages of embryonic development through to adulthood. It is a central area of study within developmental biology and neuroscience, seeking to explain how complex nervous systems arise from relatively simple groups of embryonic cells. Research in neural development spans a wide range of organisms, from nematodes and Drosophila melanogaster to vertebrates and mammals, providing comparative insights into conserved cellular and molecular mechanisms.
Disruptions in neural development can result in structural malformations of the brain and spinal cord as well as long-term neurological and cognitive disorders. These include congenital abnormalities such as holoprosencephaly, motor impairments including paresis and paralysis, sensory deficits affecting balance and vision, seizure disorders, and in humans, neurodevelopmental conditions such as Rett syndrome, Down syndrome, and various forms of intellectual disability.

Origins of the Vertebrate Nervous System

In vertebrates, the central nervous system (CNS), comprising the brain and spinal cord, originates from the ectoderm, the outermost germ layer of the early embryo. During early embryogenesis, a specialised region of the dorsal ectoderm becomes specified as neuroectoderm, forming a flattened structure known as the neural plate along the dorsal surface of the embryo. This process occurs alongside early embryonic patterning events that establish the anterior–posterior body axis.
The neural plate represents the primary source of neurons and glial cells in the CNS. As development proceeds, the plate elongates and its lateral edges elevate to form the neural groove, which subsequently folds and fuses to create the neural tube. This process, termed neurulation, is a defining event in vertebrate neural development. Once closed at both ends, the neural tube encloses embryonic cerebrospinal fluid, which plays an active role in regulating neural precursor behaviour.

Brain Vesicle Formation and CNS Organisation

As the embryo grows, the anterior portion of the neural tube expands and differentiates into three primary brain vesicles: the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain). These early vesicles undergo further subdivision and maturation to give rise to the major anatomical regions of the adult brain.
The prosencephalon divides into the telencephalon, which forms the cerebral cortex and basal ganglia, and the diencephalon, which develops into structures such as the thalamus and hypothalamus. The mesencephalon contributes to midbrain structures including the inferior colliculus, while the rhombencephalon differentiates into the metencephalon (pons and cerebellum) and myelencephalon (medulla oblongata).
The internal cavity of the neural tube becomes the ventricular system, extending from the cerebral ventricles to the central canal of the spinal cord. Embryonic cerebrospinal fluid differs in composition from adult cerebrospinal fluid and plays an important role in neural proliferation and differentiation.

Neural Stem Cells and Cellular Differentiation

The walls of the neural tube are initially composed of rapidly dividing neural stem cells. These cells drive early brain growth through repeated divisions. Over time, subsets of these cells exit the cell cycle and differentiate into neurons and glial cells, the principal cellular components of the CNS.
Following differentiation, newly generated neurons undergo cellular migration, moving from their sites of origin to their final destinations within the developing brain. This migration is essential for the correct formation of layered and regional brain structures. Once positioned, neurons extend axons and dendrites, enabling the formation of synapses and the establishment of functional neural circuits that underlie sensory processing, motor control, and behaviour.

Neural Induction

Neural induction is the process by which undifferentiated ectodermal cells are directed to become neural tissue. This process requires signals from the underlying mesoderm, particularly from a structure known as the notochord, which forms along the dorsal midline and later contributes to the vertebral column.
During gastrulation, mesodermal cells migrate beneath the ectoderm and emit diffusible signals that convert overlying ectoderm into neuroectoderm. The ability of mesoderm to induce neural fate in ectodermal tissue is a defining feature of vertebrate development. Experimental transplantation of the dorsal blastopore lip demonstrates this inductive capacity, as it can convert non-neural ectoderm into neural tissue.
At the molecular level, neural induction involves inhibition of bone morphogenetic protein (BMP) signalling. BMPs, particularly BMP4, promote epidermal differentiation in ectodermal cells. The notochord and adjacent dorsal mesoderm secrete BMP antagonists such as noggin, chordin, and follistatin, which block BMP activity and allow neural genes to be expressed. This has led to the concept that neural differentiation represents the default fate of ectoderm in the absence of BMP signalling.

Neurulation and Neural Tube Patterning

Neurulation transforms the neural plate into the neural tube, establishing the basic architecture of the CNS. The neural tube exhibits distinct dorsal and ventral regions, known respectively as the alar plate and basal plate, separated by the neural canal. The open ends of the tube, the neuropores, must close properly to prevent severe congenital defects. Failure of closure can result in fatal conditions such as anencephaly or lifelong disabilities such as spina bifida.
Once formed, the neural tube undergoes extensive patterning along both its dorsoventral and rostrocaudal axes, ensuring the correct spatial arrangement of neuronal subtypes.

Dorsoventral Patterning

Dorsoventral patterning of the neural tube is regulated by opposing signalling centres. The ventral neural tube is patterned by sonic hedgehog (Shh), secreted initially by the notochord and later by the floor plate. Shh functions as a morphogen, inducing different cell fates depending on its concentration. Low levels promote ventral interneuron development, higher levels specify motor neurons, and the highest levels induce floor plate differentiation.
Shh signalling operates through the Patched–Smoothened pathway, leading to activation of GLI transcription factors. Disruption of Shh signalling impairs ventral neural specification and is associated with severe brain malformations, including holoprosencephaly.
In contrast, the dorsal neural tube is patterned by BMPs and related signals from the overlying epidermal ectoderm. These signals induce dorsal sensory interneurons through intracellular pathways involving SMAD transcription factors.

Rostrocaudal Patterning

Patterning along the anterior–posterior axis is controlled by gradients of signalling molecules such as fibroblast growth factors and retinoic acid, particularly within the hindbrain and spinal cord. A key role in this process is played by Hox genes, which are expressed in overlapping domains along the neural tube.
Retinoic acid regulates the expression of specific Hox genes, with genes at the 3′ end of the Hox clusters activated in more anterior regions and 5′ genes expressed posteriorly. This patterned expression establishes segmental identity, particularly within the hindbrain, where distinct segments known as rhombomeres give rise to specific cranial nerves. For example, expression of Hoxb1 in rhombomere 4 is essential for proper development of the facial nerve.