P. VNormal Atrioventricular septum defect
19.2 Diff erentiation of the spinal cord
Fig. 19.1 Development of the spinal cord.
A
Alar plate (sensory)
Basal plate (motor)
B C
Ventral fissure
BMP BMP
SHH SHH
Lumen
Roof plate
Floor plate
Sulcus limitans Ependyma
Mantle layer
Development of the brain 183
fourth ventricle in the upper part of the medulla and the pons. The alar and basal plates are splayed out away from the midline plates which are pushed laterally, but the arrangement of the two plates relative to each other remains the same. Compare the position of the sulcus limitans sepa- rating the alar and basal plates in Figure 19.1 and 19.2. The alar plates now lie lateral to the basal plates. The result is that motor nuclei developing from the basal plates lie ventrally near the midline whereas sensory nuclei aris- ing from the alar plates lie more laterally and dorsally; this explains Rule 2 for determining the position of cranial nerve nuclei given in Section 18.2.2 ).
The neural crest cells that form during neurulation contribute to a large number of adult structures, especially in the head and neck (see Chapter 21 ). They contribute to the PNS throughout the body. In the trunk, neural crest tissue aggregates to form the dorsal root ganglia between somites and also autonomic ganglia. Similarly, neural crest cells form the sensory ganglia of cranial nerves and parasympathetic neurons in the head (see Chapter 21 ). Peripheral and central sensory and post- ganglionic autonomic neuronal processes develop from the ganglia.
19.2.1 Vertical specifi cation of the central nervous system
The dorsoventral organization of the nervous system begins very early in development as described in Section 8.3.3 . As described in Chapter 8 , organization of the embryo along the longitudinal axis begins even earlier as mesodermal tissues are formed during gastrulation.
Recall from Section 8.3.3 that embryonic ectodermal cells are exposed to doses of retinoic acid (RA) as they move through Hensen’s node and the primitive streak to become mesenchymal cells. Home- obox genes are activated by RA as they pass through the node. The genes closest to the 3’ end of the chromosome respond to low doses of RA whereas those nearest to the 5’ end are activated by higher doses. The fi rst cells to pass through the primitive streak receive a low dose and end up towards the future head end of the embryo; later migrating cells do not migrate so far. As Figure 19.3 shows, homeobox genes are expressed in a specifi c sequence along the anteroposterior axis of the part of the neural tube that will become the hindbrain (pons and medulla); the 3’ genes are more anterior than the 5’ genes because of their exposure to diff erent doses of RA as they migrate.
The hindbrain develops a series of segments, the rhombomeres , which can be seen clearly under a microscope; as Figure 19.3 shows, the anterior edge of each segment corresponds to the expression boundary of diff erent Hox genes. The hindbrain is the only area of the developing CNS that shows overt segmentation although similar segments can be located between diff erent parts of the developing
brain when gene expression boundaries are examined, but are not visible even under the microscope. As shown in Figure 19.3 , neural crest-derived ectomesenchymal cells migrate from particular rhom- bomeres to populate specifi c pharyngeal arches. The sensory cranial nerves develop from the neural crest cells and their motor compo- nents develop from the basal plate of rhombomeres. The Hox gene coding carried by the ectomesenchymal cells identifi es each pharyn- geal arch. Cranial nerves will only innervate derivatives of their own arch. The formation of the pharyngeal arches will be covered in more detail in Chapter 21 .
The spinal cord is not segmented, but the paraxial mesoderm forming the somites alongside the spinal cord does carry a home- obox gene code that gives the somites at diff erent levels their spe- cifi c identities. The central sensory processes developing from each dorsal root ganglion and peripheral axons of motor neurons leaving the spinal cord are channelled along specifi c routes through somites.
They can pass through the superior part but cannot pass through the inferior area of each somite. The nerves are thus directed to form bundles in the upper part of the somite which then enter or leave the spinal cord at the same level; the level of attachment of the sensory and motor components of the spinal nerves demarcates the spinal cord segments.
Brain and motor nerves
Hox gene expressions Hoxb–2 Hoxb–3 Hoxb–4 Hoxb–5 XI
XII X IX VII III
r4 r5 r6
r7 r3 r2
r1 Hindbrain
Forebrain
Eye VI
V IV
Fig. 19.3 The division of the developing hindbrain into rhombomeres and the expression boundaries of homeobox genes. (Redrawn after Noden, D.M. and Trainor P.A. Journal of Anatomy 207: 575–603 (2005)).
19. 3 Development of the brain
19.3.1 Divisions of the brain
In the early embryo, the head end of the developing neural tube tends to fold ventrally as shown in Figure 19.4A . The cephalic fl exure, marked by the ventral sulcus , probably occurs because the neural tube is growing faster than the tissues forming below it. The area anterior to the ventral sulcus enlarges into the prosencephalon or forebrain .
Figure 19.4B indicates that a second pontine fl exure occurs a little later in development posterior to and in the opposite direction to the ventral sulcus. The pontine fl exure, also known as the isthmus , sepa- rates the midbrain (mesencephalon) superiorly from the hindbrain (rhombencephalon) inferiorly. The isthmus is an organizer region
184 Development of the central nervous system
that secretes signalling molecules that specify neuroblasts superiorly to form midbrain structures and those inferior to the isthmus to form the pons and cerebellum. The boundaries between the isthmus and rhom- bomeres in the hindbrain prevent the movement of developing neurons between segments so that cells specifi ed to become certain structures remain in the correct location and do not become contaminated with cells from other sources.
In primitive vertebrates, the three gross divisions of the brain are associated with specifi c sensory inputs—olfaction from the nose to fore- brain, vision from the eye to midbrain, and hearing and balance from the ear to hindbrain. During the course of evolution, each division of the brain has developed a posterior extension to increase the number of neurons needed to cope with increasingly large inputs and to devel- op more sophisticated skills and functions. As shown in Figure 19.4C , the cerebral hemispheres developed from the forebrain, the tectum from the midbrain, and the cerebellum from the hindbrain. The basic vertebrate structure of the brain is maintained during its further embry- onic development. The front part of the hindbrain, (the metencephalon ) forms the pons with its dorsal outgrowth, the cerebellum . The cerebel- lum develops in the roof of the rhombencephalon above the anterior part of the fourth ventricle. The roof is wide posteriorly and very narrow anteriorly in this region. The narrow anterior area thickens to form the cerebellar plate . By the twelfth week of development, the developing cerebellum begins to resemble the mature structure; paired cerebellar hemispheres have started to develop laterally to the small midline ver- mis. The remainder of the rhombencephalon gives rise to the medulla oblongata .
The midbrain tectum has lost its function as the primary visual cor- tex in higher animals; echoes of its evolutionary history still remain as shown by the function of the superior colliculi as centres coordinating
refl exes in response to visual stimuli (see Section 15.3.2 ). The inferior part of the tectum (the inferior colliculi ) provides relays for the audi- tory pathway from the cochlear nuclei to the thalami.
The changes in the forebrain are even more dramatic. The dien- cephalon is the original unpaired precursor of the forebrain. As shown in Figure 19.4C , paired outgrowths from the diencephalon then grow forwards to form the cerebral hemispheres and the olfactory bulbs . These structures together make up the telencephalon . Optic vesi- cles extend from the diencephalon remaining attached by the optic stalks which later develop into the optic nerves . The distal end of each optic vesicle comes into contact with a dense sheet of surface ectoderm called the lens placode which will form the lens of the eye;
the optic vesicle becomes the retina. More inferiorly, the infundibu- lum, a precursor of the pituitary stalk, grows down towards the roof of the developing oral nasal cavity. These will later meet to form the pituitary gland .
The sequential development and changes in relationships and posi- tion of the forebrain, midbrain and hindbrain, and their derivatives are illustrated diagrammatically in Figure 19.5 .
19.3.2 Development of the cerebral hemispheres
As we saw in Chapter 15 , the cerebral hemispheres are the largest com- ponents of the human brain. As you can see in Figure 19.5 , the devel- oping hemispheres overgrow the diencephalon which becomes buried.
There is a limit to the increase in volume of the cerebral cortex which can be achieved by simple expansion. Further increase is most effi ciently achieved by folding. As described and illustrated in Chapter 15 , the sur- face of the cerebral hemispheres in the human brain and those of more
A B C
Cerebral hemisphere Olfactory bulb
Optic stalk
Tectum
Cerebellum Infundibulum
Pons Cephalic flexure
Medulla oblongata Telencephalon
Diencephalon Prosencephalon
Mesencephalon
Rhombencephalon Ventral sulcus
Pontine flexure Optic vesicle
Fig. 19.4 Development of the brain areas from the neural tube.
Neuronal connectivity 185
One of the most intriguing questions in developmental biology is how the billions of neurons that constitute the CNS make all the requisite connections with the correct structures. The same question can be asked of the connections of the central and peripheral processes of PNS neurons with the CNS and their target tissues, respectively; on the face of it, this looks a simpler problem to solve.
This is a huge topic and only a brief outline is given. As we have already seen, in the CNS, the type of neurons and their fate is determined by their developmental position in the superior to inferior and dorsal to ventral axes; diff erent populations of neurons carry identifi cation badges in the form of cell surface molecules. Essentially, the growing processes of developing neurons called growth cones carry receptors specifi c for short-range signalling molecules released by the tissues that they are advancing through. These signalling molecules attract or repel the growing neurons and, therefore, determine the direction in which growth cones advance as we have already seen for the growth of neurons through
somites. Long-range guidance cues and chemical attractants released by target neurons or target tissues act in similar ways to ensure correct connections are established between neurons and their targets. Many short-range and long-range signalling molecules actively repel unwanted neurons so that only the correct neurons get through. The way in which neurons and targets are ‘wired up’ is quite well worked out for some sys- tems but we only have a few tantalizing clues at present for others.
As neurons encounter their target and more processes join them, neuronal tracts are formed within the CNS. The growing neurons also promote the diff erentiation of glial cells that, in turn, release inhibi- tory factors that stop axons from the wrong sources joining tracts as they become established. This is an incredibly useful mechanism dur- ing development, but, as mentioned in Chapter 3 , is unfortunately not turned off when development is complete. This explains why neurons in the CNS do not re-establish connections after trauma or disease as outlined in Box 19.1 .
V VIIIX
IXX V
VII
IX
X V
VII III IX
V VII
Telencephalon Telencephalon
Diencephalon
Thalamus and hypothalamus (diencephalon) Cerebral
hemispheres (telencephalon) Diencephalon
Prosencephalon
Mesencephalon Cerebellar
rudiment Cerebellar
rudiment
Cerebellum Medulla Pons
Mesencephalon
Mesencephalon Rhombencephalon
Rhombencephalon Rhombencephalon
Fig. 19.5 The development of the brain.
advanced types of animals are folded into gyri separated by sulci; the cer- ebral surface is relatively smooth in primitive mammals. The gyral folds increase the surface area without increasing the overall volume.
The original cavity of the neural tube persists within the brain as a series of spaces fi lled with cerebrospinal fl uid. As the cerebral
hemispheres grow outwards, the cavity expands into them to form the lateral ventricles . Each of these connects with the cavity of the dien- cephalon, the third ventricle . The cavity of the midbrain is reduced to a narrow canal, the cerebral aqueduct running from the third ventricle to the fourth ventricle in the pons and medulla oblongata.
19.4 Neuronal connectivity
Box 19.1 Why do CNS neurons not regenerate after injury?
Glial inhibitory factors repel neuronal processes from the wrong source away from developing tracts and pathways. Their continued presence in the mature CNS essentially prevents regeneration of neurons and establishment of successful connections following CNS nerve injury from trauma or disease. Damaged neurons will
form growth cones on the end of any severed processes which will endeavour to make connections. However, they are inhibited at more or less every turn so wander aimlessly about, trying to make progress; they usually form tangles of blind-ending neurons close to the site of the lesion called a neuroma .
186 Development of the central nervous system
One thing that is often overlooked during consideration of neuro- nal development is the very small distances that developing neuro- nal processes have to travel between their parent cell body and their intended target in the embryo compared with the distances that sepa- rate the two ends in the mature organism. Once connections have been made, often over quite short distances, neuronal processes can grow to accommodate the increasing distance between origin and
target by adding material to their cell membranes, thus maintaining the link. This enables neurons to follow the migration and changes of position of their target tissues as they develop and grow and this is often marked by the course of nerves in the adult; the phrenic nerves supplying the diaphragm ( Chapter 10 ) and the recurrent laryngeal nerves have already been cited as examples of these phenomena ( Chapter 12 ).