The Neural Tube and Neural Crest Give Rise to the Central and Peripheral Nervous Systems

During the third week of embryonic development, in response to chemical signals released by the underlying midline mesoderm, a longitudinal band of ectoderm thickens to form the neural plate. Shortly thereafter, the neural plate begins to fold inward, forming a longitudinal neural groove in the midline flanked by a parallel neural fold on each side (Figs. 2-1 and 2-2). The neural groove deepens, and the neural folds approach each other in the dorsal midline. At the end of the third week the two folds begin to fuse midway along the neural groove at a level corresponding to the future cervical spinal cord, starting the formation of the neural tube (Fig. 2-3). Additional sites of fusion soon appear, the regions in between zip up, and the entire neural tube is closed before the end of the fourth week. This process is referred to as primary neurulation. As the neural tube closes, it progressively separates from the ectodermal (i.e., skin) surface and becomes enclosed within the body, leaving behind groups of cells from the crest of each neural fold (Fig. 2-4). These neural crest cells develop into a variety of cell types (Fig. 2-5), including the sensory neurons of the ganglia of spinal nerves and some cranial nerves,* the postganglionic neurons of the autonomic nervous system, and the Schwann cells and satellite cells of the peripheral nervous system (PNS). The neural tube develops into virtually the entire CNS; its cavity becomes the ventricular system of the brain.

Figure 2-1 The neural plate and beginning neural groove at about 18 days of development (A) and the neural groove 2 days later (B), shortly before the neural tube begins to close. The schematic cross sections to the left and right are at the levels indicated by the arrows in A and B, respectively.

(From Arey LB: Developmental anatomy, ed 4, Philadelphia, 1941, WB Saunders.)

Figure 2-2 Scanning electron micrograph of the just-closing neural tube of a chick embryo, fractured at about the level of the future midbrain.

(From the cover photograph accompanying Schoenwolf GC, Smith JL: Development 109:243, 1990.)

Figure 2-3 Neural tube closure during the fourth week. A, Neural folds begin to fuse at the cervical level of the future spinal cord at about day 21; the total length of the neural tube at this time is about 2.5 mm. B, This and additional areas of fusion expand rapidly in both rostral and caudal directions. C, By about day 24, the rostral end of the neural tube has closed; the caudal end will close about 2 days later. Even before the neural tube has finished closing, local enlargements (the primary vesicles) and bends begin to appear. The notochord is the forerunner of the skeletal axis, helping to form the vertebral column. The mesodermally derived somites, adjacent to the neural tube, go on to form most of the vertebral column, as well as segmental structures such as skeletal muscle and dermis corresponding to spinal cord segments (see Chapter 10).

(From Arey LB: Developmental anatomy, ed 4, Philadelphia, 1941, WB Saunders.)

Figure 2-4 Section through the just-closed neural tube of a chick embryo at the level of the future spinal cord. Neural crest cells are pinched off as the neural tube closes.

(From Schoenwolf GC, Smith JL: Development 109:243, 1990.)

Figure 2-5 Migratory paths and some fates of neural crest cells. Neural crest cells give rise to an extraordinary variety of tissues and structures, only some of which are indicated here.

The sacral spinal cord forms by a slightly different mechanism. After the neural tube closes, a secondary cavity extends into the mass of cells at its caudal end, in a process of secondary neurulation.

The Sulcus Limitans Separates Sensory and Motor Areas of the Spinal Cord and Brainstem

The ectoderm near what will become the dorsal surface of the neural tube, and the mesodermal notochord near the ventral surface, produce different signaling molecules early in development. The opposing concentration gradients of these signaling molecules induce distinctive patterns of subsequent development in these two regions of the neural tube (Fig. 2-6). This becomes morphologically apparent during the fourth week, when a longitudinal groove (the sulcus limitans) appears in the lateral wall of the neural tube, separating it into a dorsal half and a ventral half throughout the future spinal cord and brainstem. The gray matter of the dorsal half forms an alar plate and that of the ventral half forms a basal plate (Figs. 2-2 and 2-7). This is a distinction of great functional importance because alar plate derivatives are concerned primarily with sensory processing, whereas motor neurons are located in basal plate derivatives. In the adult spinal cord, even though the sulcus limitans is no longer apparent, the central gray matter can be divided into a posterior horn and an anterior horn on each side (Fig. 2-7C). The central processes of sensory neurons (derived from neural crest cells) end mainly in the posterior horn, which contains most of the cells whose axons form ascending sensory pathways. In contrast, the anterior horn contains the cell bodies of somatic and autonomic motor neurons, whose axons leave the spinal cord and innervate skeletal muscles and autonomic ganglion cells. The same distinction between sensory alar plate derivatives and motor basal plate derivatives holds true in the brainstem, as discussed briefly in this chapter and in more detail in Chapter 12. (The sulcus limitans does not extend beyond the brainstem, although concentration gradients of the same signaling molecules induce other distinctive dorsal-ventral patterns of development in the cerebrum. Hence the alar-basal plate distinction is not useful for cerebral structures, even though some deal primar-ily with sensory processes and others with motor processes.)

Figure 2-6 Induction of dorsal-ventral patterns of differentiation in the spinal cord by concentration gradients of signaling proteins. A, At the neural plate stage, midline mesoderm and later the notochord produce a signaling protein called sonic hedgehog protein (SHH; so named because the gene that specifies it is similar to a gene called Hedgehog that serves a similar purpose in invertebrates). Simultaneously, ectoderm adjacent to the neural plate produces another set of signaling proteins from a group called bone morphogenetic proteins (BMPs). B, Under the continued influence of the notochord, cells near the ventral midline of the neural groove begin to express sonic hedgehog themselves. Ectoderm near the crests of the neural folds continues to produce BMPs. C, After the neural tube closes, cells near the dorsal midline produce BMPs, continuing the opposing SHH-BMP concentration gradients.

(Based on a drawing in Tanabe Y, Jessell TM: Science 274:1115, 1996.)

Figure 2-7 Sulcus limitans and alar and basal plates. A, Neural tube during the fourth week. B, Embryonic spinal cord during the sixth week. Dorsal root ganglion (DRG) cells, derived from the neural crest, send their central processes into the spinal cord to terminate mainly on alar plate (AP) cells; basal plate (BP) cells become motor neurons, whose axons exit in the ventral roots. C, Adult spinal cord. The asterisk indicates the location of the central canal.

The Neural Tube Has a Series of Bulges and Flexures

The neural tube is never a simple, straight cylinder. Even before it has completely closed, bulges begin to appear in the rostral the neural tube in the region of the future brain, and bends begin to appear as well (Fig. 2-3C).

There Are Three Primary Vesicles

During the fourth week, three bulges, or vesicles, are apparent and are referred to as the primary vesicles (Fig. 2-8). From rostral to caudal, these are the prosencephalon (forebrain), the mesencephalon (midbrain), and the rhombencephalon (hindbrain), which merges smoothly with the spinal portion of the neural tube. The prosencephalon develops into the cerebrum. The mesencephalon becomes the midbrain of the adult brainstem, and the rhombencephalon becomes the rest of the brainstem and the cerebellum (Table 2-1).

Figure 2-8 Primary vesicles at the end of the fourth week. A, Lateral view of the neural tube, showing vesicles and flexures. B, Schematic longitudinal section, as though the flexures had been straightened out.

(A, modified from Hochstetter F: Beiträge zur Entwicklungsgeschichte des menschlichen Gehirns. I. Teil, Vienna, 1919, Franz Deuticke.)

Table 2-1 Derivatives of Vesicles of the Neural Tube

The three primary vesicles are not arranged in a straight line; rather, they are associated with two bends or flexures in the neural tube (Fig. 2-8A). One of these, the cervical flexure, occurs between the rhombencephalon and spinal cord but straightens out later in development. The second, the cephalic (or mesencephalic) flexure, occurs at the level of the future midbrain and persists in the adult as the bend between the axes of the brainstem and the cerebrum (see Fig. 3-1).

There Are Five Secondary Vesicles

As the brain continues to develop, two of the primary vesicles become subdivided. During the fifth week, five secondary vesicles can be distinguished (Fig. 2-9). The prosencephalon gives rise to the telencephalon (Greek for “end brain”) and the diencephalon (Greek for “in-between brain”); the mesencephalon remains undivided; the rhombencephalon gives rise to the metencephalon and the myelencephalon. The telencephalon becomes the cerebral hemispheres of the adult brain. The diencephalon gives rise to the thalamus (a large mass of gray matter interposed between the cerebral cortex and other structures), the hypothalamus (an autonomic control center), the retina, and several other structures. The metencephalon becomes the pons (part of the brainstem) and the cerebellum. The myelencephalon be-comes the medulla (the part of the brainstem that merges with the spinal cord).