Holoprosencephaly
Although we have been focusing on the anterior-posterior and dorsal-ventral specification of the neural tube, the right-left axis is also important, especially with regards to the prosencephalon. Unlike the other brain ventricles, the prosencephalon divides into a right and a left hemisphere, connected by the corpus callosum. The mechanisms by which the prosencephalon splits and the corpus callosum forms is being investigated by looking at those human conditions where these events fail to occur.
Phenotypic heterogeneity and holoprosencephaly
Holoprosencephaly is characterized by the incomplete cleavage of the forebrain (prosencephalon) into right and left hemispheres, into diencephalon and telencephalon, and into olfactory and optic bulbs. Holoposencephaly is characterized by a remarkable amount of phenotypic plasticity. Depending upon othergenes (and probably environmental factors), the same loss-of-function allele can give a wide variety of phenotypes. The holoprosencephalic conditions are graded from the most severe cases (which are lethal) to mild abnormalities only recognizable by physicians looking for such things. The most severe type, where a single forebrain vesicle is formed without any evidence of division into left or right hemispheres, is cyclopia. Here, a nose-like proboscis extends over a single, medial eye (Figure 1A,B). The next grade of holoprosencephaly is called ethmocephaly, where the closely-spaced eyes are in separate orbits but are separated only by the proboscis (Figure 1C). The third level of holoprosencephalic conditions is cebocephaly, wherein the closely spaced eyes are above a nose with a single nostril (Figure 1D). In these above three cases, the prosencephalon has not divided to form the left and right hemispheres.
In the next grades of holoprosencephaly, the prosencephalon has split to a varying, but not yet normal, degree. In the fourth level of holoprosencephaly, the eyes are still close together, the nose is flat, and there is a medial cleft lip (Figure 1E,F), and in the fifth level, there is a bilateral cleft lip, closely spaced eyes, and a flat medial process representing the philtrum. The lesser grades of holoprosencephaly include various "midline" abnormalities including closely or widely spaced eyes (Figure 1G,H) and dental anomalies such as a single central incisor (Figure 1I).
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| Figure 1 The phenotypic spectrum of holoprosencephaly. (From Muenke, 1995.) |
Some cases of holoprosencephaly are sporadic, but there are some families wherein holoprosencephaly is an inherited condition. This extreme variation of clinical features associated with holoprosencephaly can also occur within a family. Several genes have been implicated in causing this condition, and the wild-type alleles at these loci are hypothesized to be crucial for normal forebrain development (Muenke, 1989, 1995).
Genetic heterogeneity in holoprosencephaly
The identities of these genes are being determined by positional gene cloning and candidate gene mapping. In several families, holoprosencephaly correlates with a broken chromosome. One of these breaks is at position 2p21, while another is at position 7q36. It is thought that these breaks interrupt the genes for normal neural tube development. The gene on chromosome 2 has been shown to be the SIX3 gene (Wallis et al., 1996). This gene is homologous to the sina oculis gene in Drosophila, which is also involved in eye formation. When Six3 is misexpressed in mice, it causes the formation of ectopic retinae. The gene in chromosome 7 turned out to be Sonic Hedgehog (Roessler et al., 1996). As discussed in the textbook, Shh is critical in separating the original anterior eye field into two lateral eye fields. Another group of patients with holoprosencephaly turned out to have a defect in the SMAD2 (TGIF) gene that is downstream of Nodal signaling (Gripp et al., 2000).
Holoprosencephaly has also been seen as part of a syndrome called the Smith-Lemli-Opitz (SLO) Syndrome. This syndrome has been found to be caused by loss-of-function alleles of the sterol delta-7-reductase gene (DHCR7) gene. This gene encodes the enzyme that is critical in cholesterol synthesis. Since cholesterol is a cofactor in sonic hedgehog production and reception (it helps split the Shh protein into its mature form, and it aids the Patched protein in its ability to transmit the signal to smoothened), the lack of cholesterol can proiduce the same types of phenotypes as the lack of sonic hedgehog. Indeed, using drugs to deprive pregnant mice of cholesterol will produce such syndromes in their offspring (Porter, et al., 1996; Dehart, 1997; Kelly, 1998)
Environmental causation
In addition to the genetic component to holoprosencephaly, environmental factors are also critical. Several teratogens can cause holoprosencephaly, one of them being the alkaloids of the plant Veratum californicum and another being ethanol. In both instances, it is thought that these drugs affect the prechordal mesoderm during gastrulation and/or the neural plate during early neurulation (Cohen et al., 1992). As mentioned in the textbook, Veratrum alkaloids, such as cyclopamine block cholesterol synthesis and function (Incardona et al., 2002).
Thus, holoprosencephaly shows phenotypic heterogeneity (one gene causing different phenotypes depending on the other genes in the organism), genetic heterogeneity (different genetic loci being able to create the same abnormal phenotype), and environmental causation (wherein teratogens are able to disrupt the genetic pathways required to form the normal phenotype).
Agenesis of the Corpus Callosum
Genetic analysis has also excluded similar diseases that are caused by different pathways. Although the failure to form the corpus callosum may appear superficially similar to holoprosencephaly, the two turn out to be radiacally different disases. The rudiment of the corpus callosum arises from the dorsal portion of the rostral wall of the telencephalon. This anlage proliferates to form a homogeneous cellular mass called the lamina reuniens (Figure 2). As the forebrain ventricle divides into the two hemispheres and the inter-hemispheric fissure deepens, a longitudinal groove develops within the dorsal part of the lamina reuniens, drawing the walls of the ventricles towards one other. At 10 weeks gestation, the walls of the groove and the meninges between them degenerate, and the two sides of the groove fuse to form a band known as the massa commissuralis. The nerve fibers of the anterior commissure neurons had been growing towards the midline for four weeks, and they are now able to cross over. At 11 weeks, fibers crossing dorsally to the anterior commissure fibers form the hippocampal commissure. Soon afterwards, more fibers cross between these two commissures to form the definitive corpus callosum.
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| Figure 2 Schematic drawing of the anterior midline of the human brain at 11-12 weks gestation. (A) Sagittal view, showing the location of the anlage of the major commissures, including the corpus callosum. (B) Coronal views, showing the folds of the lamina reuniens which will soon fuse to form the massa commissuralis. (AC, anterior commissure; CC, corpus callosum; F, fornix; HC, hippocampal commissure; LR, lamina reuniens; LT, lamia terminalis; MC, massa commissuralis; OC, optic chiasma; SA, septal area; sulcus, sulcus medians telencephali medii). (After Dobyn, 1996.) |
Linkage studies (Casaubon et al,, 1996) indicated that a gene responsible for this syndrome mapped to a 5-cM region on 1the long arm of chromosome 15. Howard et al. (2002a) limited this area to only 2-cM. This is where a gene, KCC3 was located. KCC3 encodes a potassium-chloride cotransport ion pump. Indeed, when families having this disease were screened, mutations were found in this gene (Howard et al., 2002b).
Literature Cited
Casaubon, L. K. and ten others. 1996. The gene responsible for a severe form of peripheral neuropathy and agenesis of the corpus callosum maps to chromosome 15q. Am. J. Hum. Genet. 58: 28–34.
Cohen, M. M. Jr., and Sulik, K. K. 1992. Perspectives on holoprosencephaly. II. Central nervous system, craniofacial anatomy, syndrome commentary, diagnostic approach, and experimental studies. J. Craniofac. Genet. Dev. Biol. 12: 196–244.
Dehart, D. B., Lanoue, L., Tint, G. S., and Sulik, K. K. 1997. Pathogenesis of malformations in a rodent model for Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 68: 328–337.
Dobyns, W. B. 1996. Absence makes the search grow longer. Am. J. Hum. Genet. 58: 7–16, 1996.
Gripp, K. W. and eleven others. 2000. Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. Nature Genet. 25: 205–208, 2000.
Howard, H. C., Dube, M.-P., Prevost, C.,Bouchard, J.-P., Mathieu, J., and Rouleau, G. A. 2002a. Fine mapping the candidate region for peripheral neuropathy with or without agenesis of the corpus callosum in the French Canadian population. Europ. J. Hum. Genet. 10: 406–412.
Howard, H. C, and twenty-four others. 2002. The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nature Genet. 32: 384–392. Corrigendum: Nature Genet. 32: 681.
Incardona JP, Gruenberg J, Roelink H. 2002. Sonic hedgehog induces the segregation of patched and smoothened in endosomes. Curr. Biol. 12: 983–995.
Kelley, R. I. 1998. RSH/Smith-Lemli-Opitz syndrome: mutations and metabolic morphogenesis. (Editorial) Am. J. Hum. Genet. 63: 322–326, 1998.
Muenke, M. 1989. Clinical, cytogenetic, and molecular approaches to the genetic heterogeneity of holoprosencephaly. Amer. J. Med. Genet. 34: 237–245.
Muenke, M. 1995. Holoprosencephaly as a genetic model for normal craniofacial development. Semin. Dev. Biol. 5: 293–301.
Roessler, E., Belloni, E., Gaudenz, K., Jay, P., Berta, P., Scherer, S, W., Tsui, L.-C., and Muenke, M. 1996. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nature Genet. 14: 357–360, 1996.
Porter, J. A., Young, K. E., and Beachy, P. A. 1996. Cholesterol modification of hedgehog signaling proteins in animal development. Science 274: 255–258.
Wallis, D. E., and nine others. 1999. Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nature Genet. 22: 196–198.