Development of the brain

Neural tube formation

The central nervous system is derived from the neural tube, which appears during the fourth week after fertilization. At this early stage the embryo takes the form of a trilaminar germ disc, lying in the floor of the amniotic sac (Fig. 2.1). The germ disc is composed of three layers of tissue from which all the structures of the body originate:

Fig. 2.1 The trilaminar germ disc in the floor of the amniotic sac, bisected in the coronal plane.
**(A)** The germ disc is composed of three primitive germ layers from which all body tissues are derived. A complex process of folding (not illustrated) transforms the germ disc so that the ectoderm comes to lie on the outside and the endoderm lines the gut lumen; **(B)** The body can be represented in cartoon form as a hollow cylinder with the mouth at one end and the anus at the other.

The ectoderm (Greek: ektos, outside) contributes mainly to the skin, but also gives rise to the central and peripheral nervous systems.

The mesoderm (Greek: misos, middle) is the origin of the cardiovascular, musculoskeletal, urinary and reproductive systems.

The endoderm (Greek: endon, within) contributes chiefly to the respiratory and gastrointestinal tracts, including the liver, gallbladder and pancreas.

The process by which the embryonic ectoderm gives rise to the neural tube is called primary neurulation (Fig. 2.2). It is initiated by the notochord, a rod-like mesodermal structure that helps to define the longitudinal axis of the embryo. The notochord releases soluble mediators including cell adhesion molecules and trophic factors, which influence the overlying ectoderm. This process is termed neural induction.

Fig. 2.2 The origin of the neural tube and neural crest.
**(A)** The mesodermal notochord releases soluble mediators that induce neural tube formation in the overlying ectoderm (neural induction); **(B)** The neural tube forms from the paired neural folds which flank the neural groove; **(C)** The neural crest cells detach from the dorsolateral margins of the neural tube and will give rise to much of the peripheral nervous system, including the spinal and autonomic ganglia.

Ultrasound studies show that in humans the neural tube begins to form at around 21-23 days after fertilization, when the embryo is just 2–3 mm in length. The first change (which occurs at about day 18) is the appearance of the neural plate, a broad area of thickening in the dorsal ectoderm. A shallow longitudinal depression termed the neural groove separates the neural plate into paired neural folds which gradually roll up to form a cylinder. The neural folds ultimately meet in the midline and unite to create the neural tube and neural canal. Fusion begins in the presumptive cervical region and proceeds both rostrally and caudally in a ‘zipper-like’ fashion. The open ends of the neural tube are called the cranial and caudal neuropores, which have normally closed by the beginning of week five. Disorders resulting from faulty neural tube closure are discussed in Clinical Box 2.1.

Clinical Box 2.1: Neural tube defects

Incomplete closure of the neural tube is responsible for a group of developmental disorders called neural tube defects. The incidence is approximately 1 in 500 live births. The most common form is spina bifida which results in malformation of the lower spinal cord due to abnormal caudal neuropore closure. The severity is variable, ranging from little or no neurological impairment to paralysis of the lower limbs with lack of bladder and bowel control. An asymptomatic partial form that only affects the vertebral arches (spina bifida occulta) is present in up to 10% of the population. Defective closure of the cranial neuropore can lead to anencephaly in which the forebrain fails to develop (Greek: a-, without; enkephalos, brain). Anencephalic fetuses are often stillborn, but may survive for a few hours after birth. It has been shown that folic acid supplements in women of child-bearing age reduce the incidence of neural tube defects by around 70%.

The sacral and coccygeal segments derive from the caudal eminence, a solid mass of cells that arises just below the developing neural tube and ultimately fuses with it. A central cavity forms within the caudal eminence and becomes continuous with the central canal of the spinal cord. This process is termed secondary neurulation.

Origin of neurons and glial cells

The wall of the neural tube can be divided into three concentric zones (Fig. 2.3). The ventricular zone is closest to the fluid-filled neural canal (which will become the cerebral ventricles) and is composed of proliferating neural progenitor cells. These include neuroblasts (neuronal precursors) and glioblasts (glial precursors) that give rise to most of the specialized cells of the central nervous system. Microglia are the resident phagocytes of the brain, but originate from the bone marrow and are of mesodermal rather than ectodermal lineage.

Fig. 2.3 Transverse section through the neural tube, illustrating the ventricular, intermediate and marginal zones.
Cell division (mitosis) occurs in the ventricular zone, giving rise to neurons and glia.

Cells that have arisen in the ventricular zone migrate outwards through the wall of the neural tube. This is facilitated by radial glia which provide a ‘scaffold’ along which cells are able to crawl, guided by signalling molecules. Neurons and glial cells accumulate in the intermediate zone of the neural tube where they extend processes and begin to make connections with other cells. The outermost layer is the marginal zone. It is relatively cell-poor and is mainly composed of neuronal and glial processes.

Formation of the cerebral cortex

The three-layered arrangement of the neural tube is modified extensively to form the brain. In the developing cerebral hemispheres there is a second (superficial) neuronal layer called the cortical plate which is the precursor of the cerebral cortex. Beneath it is a transient structure called the subplate.

Cortical neurons arise in the ventricular zone (referred to as the germinal matrix in the brain) and migrate along radial glia to enter the cortical plate – or form transient connections within the subplate. Those neurons that will ultimately occupy the deepest of the six cortical laminae arrive first, with more superficial layers being added in sequential waves of neurogenesis and migration. This means that the cerebral cortex is constructed ‘inside-out’.

Proper neuronal migration depends on a layer of Cajal–Retzius cells (pronounced: ka-HARL) located in the most superficial part of the cerebral cortex. The outward migration of newly formed neurons is regulated by the protein reelin, a molecular ‘stop-signal’ that is secreted by Cajal–Retzius cells. This ensures that neurons reach the appropriate layer of the cerebral cortex.

In the cerebral hemispheres the majority of neurons ultimately vacate the intermediate zone or undergo programmed cell death (see Ch. 8) and this region eventually becomes the subcortical white matter. Up to 50% of neurons produced in the developing brain fail to (i) reach their intended targets or (ii) make appropriate functional connections and are consequently deleted by programmed cell death.

Sensory and motor areas

The neural tube has two functional divisions, separated by the sulcus limitans (Fig. 2.4A). The basal plate occupies the ventral portion of the neural tube (anterior to the sulcus limitans) and is predominantly a motor structure; the alar plate is located dorsally and is sensory. This dorsal–ventral division between sensory and motor areas is reflected in the adult spinal cord, with sensory fibres entering via the dorsal roots and motor fibres emerging in the ventral roots (Fig. 2.4B). It is echoed throughout the central nervous system so that motor structures (e.g. cortical areas, tracts, nuclei) tend to be anterior to sensory structures.

Fig. 2.4 Transverse sections through (A) the developing neural tube and (B) the adult spinal cord.
The basal (motor) plate is separated from the alar (sensory) plate by the sulcus limitans.

The neural crest

The peripheral nervous system is mainly derived from the neural crest. This is a population of cells that detaches from the lateral margins of the neural plate during neurulation (see Fig. 2.2). Neural crest cells that come to lie dorsolateral to the neural tube ultimately become the primary sensory neurons of the dorsal root ganglia. These neurons are initially bipolar but their central and peripheral processes fuse at a common T-shaped extension of the cell body to form a single continuous axon. For this reason they are described as pseudounipolar (Greek: pseudo-, false). The central processes of the dorsal root ganglion cells innervate the alar (sensory) plate of the neural tube, whereas the peripheral processes enter the spinal nerves at each segmental level (see Fig. 2.4B).

The ventral roots of the spinal nerves represent the axons of basal plate motor neurons. The primary sensory neurons of cranial nerve ganglia are also crest-derived, although not all cranial nerves carry sensory fibres. Other neural crest derivatives include the ganglia of the autonomic nervous system, peripheral Schwann cells and the inner two meningeal layers (pia and arachnoid). In contrast, the dura is a mesodermal derivative. The neural crest also gives rise to non-neural structures including skin melanocytes and components of the laryngeal cartilages and teeth.

Key Points