Q J Med 2002; 95: 415-416
© 2002 Association of Physicians
Biologic |
Ahead of the head
In a previous article in this series,1 I discussed the problems of pattern formation in the central nervous system (CNS) and left the forebrain out; it is different, complicated, poorly understood and thus easy to speculate about. With the recent controversy concerning the treatment of a child with a severe abnormality of the face, head and neck, it now seems appropriate to tackle part of this problem. How do such anomalies develop, and what have apparently mesodermal (even neuromesodermal) defects to do with the brain?
The pattern-determining mechanisms operating in the rest of the CNS do not include the forebrain, whose marked expansion in vertebrates depends on other processes. Its components (cerebral cortex, eye, basal ganglia, thalamus and hypothalamus) are not underlain by the notochord that plays a central role in medial cell differentiation in the rest of the CNS. In its absence, other signals operate, including specific epithelial signals from the placodes, necessary for the proper formation of the retina and olfactory bulb, and from Rathke's pouch in the formation of the posterior pituitary. A number of other signalling factors, including some from the neural crest, are also important.
A particular population of neuromesenchymal cells from the neural crest (neural crest cells, NCCs) is vital in forebrain development. If the rapidly expanding forebrain is to survive early development, it must be surrounded by the NCC-derived mesenchyme that forms the leptomeninges—a primitive meninx splits into two layers, giving rise to bones and to the meningeal coverings of the brain (with a contribution from the paraxial mesoderm). The developing forebrain is covered by NCCs migrating from the region of the posterior diencephalon and the mesencephalon. The paraxial mesodermal component provides the endothelial cells of included vessels; the NCCs produce the pericytes and connective tissue. Surgical removal of the NCC population results in massive cell death in the forebrain and the production of cyclops.2
Hox genes expressed in the hindbrain are expressed in both the rhombomeres and in the NCCs that they produce. There are thus two domains within NCCs that give rise to the facial and cranial skeleton: an anterior rostral domain that does not express Hox (the membrane bones of the neurocranium, the malleus and incus and the maxilla); and a posterior Hox-positive domain (mandible, stapes and facial cartilages). Hox-expressing NCCs transposed anteriorly to the Hox-negative domain fail to differentiate into cartilage and bone,3 but NCCs of the Hox-negative domain transplanted posteriorly respond to local cues.4
The paraxial mesoderm that gives rise to the posterior part of the skull (including the otic capsule, the occipital bone, part of the sphenoid and postorbital bones) covers only the midbrain and hindbrain. As a result, the anterior and posterior halves of the Circle of Willis, and the vessels they supply, derive from different cell populations. Whereas cells derived from paraxial mesoderm form the vessels that supply the posterior (dorsal) part of the head and neck, in the anterior cerebral circulation that supplies the ventral (face) part of the head and neck, the pericytes and smooth muscle cells derive from NCCs.
Etchevers et al.2 have suggested that this may indicate the point from which a new part of the head expanded in vertebrates, and that the primitive forebrain of the cephalochordates develops into the typical vertebrate forebrain (in particular the telencephalon) as a result of a change in blood supply that permits its increased integrative functions. Gans and Northcutt5 have suggested that the formation of the skeletal and muscular parts of the jaws from NCCs increased vertebrate range and success by increasing feeding capacities.
Failure of the anterior part of this process is embryo-lethal, but survivors of failure of the more posterior components of the NCC contribution have severe craniofacial anomalies (the Waardenberg, DiGeorge, Treacher Collins, Goldenhar, and Pierre Robin syndromes) and entities such as frontonasal dysplasia. Certain aortic arch syndromes also involve maldevelopment of the next most caudal part of the neural crest. All these anomalies are related in pathogenesis; in more than 80% of individuals with the velo-cardio-facial or DiGeorge syndromes and cono-truncal anomalies, there are microdeletions of one allele of chromosome 22q11.2.6 This group is sometimes known as CATCH-22 (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, hypocalcaemia, and microdeletion of chromosome 22). A combination of changes in neural crest and mesoderm is involved, and although the crest is a principal target in retinoic acid embryopathy (which can reproduce phenocopies of these anomalies7,8), the mesoderm has a central role.
More than three decades ago, Marin-Padilla9,10 emphasized the importance of neural anomalies in association with skeletal and oropharyngeal defects in the embryogenesis of these malformations, pointing out that the separately formed axial basicranium (skull base), neurocranium (cranial vault) and visceral cranium (the facial skeleton) are all affected differently in the various syndromes. The paraxial mesoderm that accumulates around the anterior end of the notochord forms much of the axial chondrocranium, including the sphenoid bone. The occipital bone is part of this structure, and a component of the segmented mesoderm may contribute to it—the occipital bone behaves like vertebrae in certain of the chondrodystophies (see also reference 11). In the mouse, homeotic transformation of the occipital bones of the skull, by ectopic expression of Hox-4.2 rostral to its normal boundary of expression, produces occipital bones changed into a more posterior phenotype, to structures resembling cervical vertebrae.12 The corresponding change in the neocranium resembled a form seen in more primitive vertebrates. These anomalies were accompanied by failures of facial development.
It is perhaps facile to say that the integrated development of NCC- and CNS-derived tissue is necessary to form a normal face. Small disturbances in positional information may have severe consequences in terms of phenotype, and detailed studies have determined the stages at which developmental failures occur. The resultant deformities are difficult to correct, because of the complex failures that result from these ‘small’ changes.
References
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