The Formation and Differentiation of the Neural Tube and Neural Crest Cells

The formation and development of the neural plate begins in the fourth week of embryonic development. At this stage, the neural plate consists of a broader cranial portion, which will eventually become the brain, and a narrower caudal portion, which will form the spinal cord. On day 22, the cephalic end of the embryo undergoes ventral flexion, known as the mesencephalic flexure, which indicates the future location of the midbrain. The cranial portion above the flexure becomes the prosencephalon (forebrain), while the caudal portion becomes the rhombencephalon (hindbrain). The rhombencephalon is further divided into segments called rhombomeres. By day 22, four rhombomeres are visible, and this increases to seven or eight by day 26.

The caudal portion of the neural plate, which represents the future spinal cord, is initially narrower and accounts% of the plate's length on day 22 (with eight pairs of somites). However, as the somites develop and evolve, the caudal portion elongates more rapidly than the cranial portion. By day 23-24 (with 12-20 pairs of somites), the future spinal cord occupies 50% of the length of the neural plate, and by day 26 (with 25 pairs of somites), it occupies approximately 60%. This rapid elongation is believed to be dependent on the elongation of the underlying notochord.

Neurulation, a crucial event in the fourth week, occurs on day 22. During neurulation, the cranial portion of the neural plate at the level of the first five pairs of somites undergoes a transformation into a neural tube. The process begins with ventral folding along the midline of the neural plate, forming a median neural groove. This groove develops in response to the induction influenced by the adjacent notochord. The two edges of the neural groove, known as neural folds, rotate around the groove like closing book pages. As the folds rotate, they become concave inward, and the lips of the folds meet dorsally to create a neural tube. The fusion of the lips of the neural folds causes the opposite edges of the ectoderm surface to meet and fuse. The ectoderm then reforms above the neural tube and separates from it.

Neurulation is the process in which the neural plate bends due to the rapid growth of the embryonic axis. This bending is influenced by the differential growth of different neuroectodermal regions, changes in the conformation of neuroepithelial cells, and the activity of microtubules and microfilaments.

During neurulation, the newly formed neural tube connects with the amniotic cavity through wide openings called neuropores. These neuropores gradually become smaller as neurulation progresses. The cranial neuropore closes on day 24, followed by the closure of the caudal neuropore on day 26. The closure of the cranial neuropore occurs in the area of the future anterior brain, while the closure of the caudal neuropore ends at the level of the second sacral segment.

Abnormal closure of the neural tube can result in developmental abnormalities in the central nervous system and morphological anomalies in vertebral arches, such as spina bifida and anencephaly.

The neural tube is fully formed after the closure of the caudal neuropore on day 26, at the level of the 31st pair of somites.

Secondary neurulation is a process that occurs during the development of the neural tube. It is believed to be formed from the regressing primitive streak on day 20. This process begins with the transformation of a mass of mesodermal tissue in the caudal eminence into a solid neural cord. This cord later forms a central cavity, which fuses with the neural tube. By the end of the sixth week, the caudal portion of the neural tube is fully formed. The regression of this part of the neural tube gives rise to the caudal extensions of the spinal cord coverings and the filum terminale. The caudal eminence also produces somites at the lower levels of the embryo.

During neurulation, neural crest cells detach from the edges of the neural folds and migrate to different parts of the body. These cells first differentiate in the mesencephalic region and then in the cranial and caudal regions. In the spinal cord region, neural crest cells detach as the lateral lips of the tube fuse.

Studies on human embryos have provided information on the migration and potential development of human neural crest cells, as well as their differentiation into non-nervous elements.

The cephalic neural crest is responsible for giving rise to various structures of the head and neck. These neural crest cells detach from the neural folds and migrate through a space located immediately below the ectoderm and within the loose mesoderm or mesenchyme of the head and neck. Additionally, neural crest cells from the folds of the mesencephalon and caudal prosencephalon give rise to tissues such as the parasympathetic ganglion of cranial nerve III, the connective tissue around the developing eye and optic nerve, iris and ciliary muscles of the eyeball, part of the head mesenchyme, and the pia mater and arachnoid in the occipital region. It is important to note that the dura mater arises from the para-axial mesoderm.

Neural crest cells from the mesencephalon and rhombencephalon region give rise to the developing pharyngeal arches of the head and neck, including the cartilaginous rudiments of several bones. These cells also form the dermis, smooth muscles, adipose tissue, and odontoblasts of developing teeth in the face and neck. Additionally, neural crest cells from the caudal portion of the rhombencephalon can give rise to the "C" cells of the thyroid.

Neural crest cells of the rhombencephalon contribute to the formation of several ganglia of the cranial nerves. They give rise to the neurons and glial cells of the parasympathetic ganglia of cranial nerves VII, IX, and X, as well as some neurons and all glial cells of the sensory ganglia of cranial nerves V, VII, IX, and X. Some distal sensory neurons of these cranial nerves originate from ectodermal placodes.

The occipital and spinal crests are responsible for the development of major components of the peripheral nervous system. This includes sensory peripheral neurons, sympathetic motor peripheral neurons, and parasympathetic motor peripheral neurons. All three types of neurons, along with associated glial cells, are derived from neural crest cells.

The spinal ganglion is derived from the spinal neural crest. Neural crest cells that originate from the spinal neural tube gather together, forming clusters that correspond with the somites. These clusters then differentiate into segmental dorsal root ganglia of the spinal nerves, which transmit impulses to the spinal cord. It has been shown that the majority of cells in each ganglion are derived from the corresponding neural tube, although some may come from the neural crest adjacent to the caudal portion of the preceding somite.

Migratory neural crest cells prefer to move through the cranial half of the sclerotomes. The survival and differentiation of ganglionic dorsal roots may depend on brain-derived neurotrophic factor (BDNF), which is secreted by the adjacent neural tube.

The parasympathetic system is formed by the development of ganglionic dorsal roots at each segmental level, except for the first cervical level and the second and third coccygeal levels. This results in the formation of 7 cervical pairs, 12 thoracic pairs, 5 lumbar pairs, 5 sacral pairs, and one coccygeal pair of ganglionic dorsal roots. The first pair of cervical dorsal roots appears on day 28, with the others forming in a craniocaudal succession over the next few days.

The distal parasympathetic neurons of the viscera derive from the occipito-cervical and sacral neural crests. Multiple peripheral motor neurons of the autonomous parasympathetic nervous system, originating from neural crest cells, migrate into the developing walls of the viscera such as the heart, stomach, and urinary bladder. These neurons form the parasympathetic motor innervation of the respective viscera, with their cell bodies located in the peripheral parasympathetic ganglia. Neural crest cells from the occipito-cervical region migrate into the mesenchyme of the intestinal wall to innervate all regions of the digestive tube, while parasympathetic ganglion cells in the lower regions of the intestine have a dual origin from the occipito-cervical and sacral neural crests.

The peripheral parasympathetic ganglia in the walls of the digestive tube and its appendages, known as enteric ganglia, are connected to the central nervous system through axons that are part of the vagus nerve (X) or the spinal nerves at the sacral levels S2, S3, and S4. The parasympathetic system is active during periods of relaxation and stimulates the visceral organs to perform their functions of digestion and food storage. The preganglionic neurons of the system are located in the cranial and sacral regions of the central nervous system, giving rise to the name craniosacral for the parasympathetic vegetative system.

The sympathetic system is formed by distal sympathetic neurons located in the ganglion chains of the sympathetic autonomous system. These ganglia are connected to the thoracolumbar central nervous system (CNS) through sympathetic preganglionic fibers. Neural crest cells from the spinal cord migrate to areas ventral to the ganglionic roots, forming condensations that give rise to the ganglion chains.

In the thoracic, lumbar, and sacral regions, a pair of ganglia is formed for each pair of somites. In the cervical region, only three large ganglia develop, while in the coccygeal region, one ganglion is formed. Studies using cellular markers have shown that neural crest cells for the cervical ganglia originate from the cervical neural tube, while the thoracic, lumbar, and sacral ganglia come from corresponding neural crest levels. Unlike the ganglionic dorsal root, the ganglionic sympathetic chain does not rely on BDNF for survival but may depend on other factors like insulin-like growth factor.

The neurons in the ganglion chain become peripheral neurons of the sympathetic peripheral nervous system. The sympathetic system provides innervation to the same structures as the parasympathetic system and controls functions like heart rate, glandular secretion, and intestinal movements. It is activated in "fight-or-flight" situations, having opposite effects to the parasympathetic system.

The efferent pathway of the sympathetic system consists of two neurons, with the viscera being innervated by axons of distal postganglionic neurons. These postganglionic neurons receive axon fibers from central proximal (preganglionic) neurons located in the spinal cord, specifically in the 12 thoracic levels and the first 3 lumbar levels. Due to this arrangement, the sympathetic system is referred to as thoracolumbar.

The pre-visceral sympathetic system is comprised of peripheral sympathetic neurons located in the ganglion chain. These neurons originate from neural crest cells that aggregate near branches of the dorsal aorta. Specifically, a pair of prevertebral or preaortic ganglia develop from the cervical neural crest at the level of the celiac trunk. Additionally, more diffuse ganglia form in association with the superior mesenteric artery, renal arteries, and inferior mesenteric artery, originating from thoracic and lumbar neural crest cells.

Aside from neurons, the neural crest also gives rise to other non-neuronal structures. This includes the inner and middle layers of the spinal meninges (pia mater and arachnoid) as well as glial cells of the ganglia derived from the spinal neural crest. Some of these glial cells have the ability to differentiate into Schwann cells, which are responsible for forming the myelin sheath of peripheral nerves. Furthermore, the neural crest also gives rise to neurosecretory chromaffin cells of the adrenal medulla, melanocytes (pigment cells of the skin), and cells of the cardiac valves.

The cytodifferentiation of the neural tube begins in the rhombencephalic region after the fusion of the occipito-cervical neural folds. It then continues cranially and caudally as the neural tube forms and grows. Neuroepithelial cells in the neural tube elongate before undergoing mitosis. The first wave of differentiation results in the formation of neuroblasts, which will become the future neurons of the central nervous system (CNS). As neurons form, the neural tube stratifies into three layers: the internal (ventricular) layer, the middle layer containing neuronal cell bodies, and the external (marginal) layer with nerve fibers. Subsequent waves of mitosis and differentiation give rise to glioblasts, which produce various types of support cells in the CNS.

The cytodifferentiation process occurs through the proliferation of the neuroepithelial cell layer, known as the ventricular layer, which makes up the neural tube. This layer differentiates into the precursors of most cell types in the future CNS, including neurons, certain types of glial cells, and ependymal cells. The first wave of cells produced in the ventricular layer forms neuroblasts, which are precursor cells of neurons. These neuroblasts migrate to the periphery of the neural tube and form the second layer called the mantle. The mantle, located external to the ventricular layer, contains neuronal cell bodies and will eventually become the gray matter of the CNS. The neuronal processes extending from the mantle to the periphery form the third layer called the marginal layer. Unlike the mantle layer, the marginal layer does not contain neuron cell bodies and will develop into the white matter of the CNS.

Neural tube cytodifferentiation involves the production of different types of cells in the spinal cord. Initially, the neuroepithelial layer produces neuroblasts, which later differentiate into glioblasts. These glioblasts give rise to various types of glial cells, including astrocytes and oligodendrocytes, which provide support to neurons. Additionally, the neuroepithelial layer differentiates and produces specialized ependymal cells responsible for the production and resorption of cerebrospinal fluid (CSF).

During the fourth week, neuroblasts in the mantle layer of the spinal cord organize into four columns: dorsal or alar columns and ventral or basal columns. The alar and basal columns are separated by the sulcus limitans. The ventral columns develop into somatic motor neurons that innervate voluntary striated muscles, while the dorsal column differentiates into association neurons that connect motor neurons with sensory neurons.

In specific regions of the spinal cord, neuroblasts from dorsal regions of the basal columns divide to form intermediate cell columns. The intermediolateral cell columns in the thoracic and lumbar regions contain autonomic motor neurons of the sympathetic system.

Overall, motor neurons generally form before sensory elements in the CNS.

References

1. Anatomia Omului, Volumul I: Embriologie; Semestrul I; Prof. univ. dr. med. Andrei Motoc; Editura „Victor Babeș”, Timișoara, 2018

2. Embriologie - Sinteze didactice; Romeo Chiriac, Anca Indrei ;Editura Fundatiei Chemarea, Iasi, 1997

3. Embriologie Umană; Lidia Chircor, Loredana Surdu;Editura Ex Ponto, Constanța, 2014

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