Review
Genetics of ventral forebrain development and holoprosencephaly

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Abstract

The disease holoprosencephaly is the basis of the most common structural anomaly of the developing forebrain in humans. Numerous teratogens when administered during early gastrulation, have been associated with this condition. Recent studies have characterized molecules expressed in the prechordal plate which are critical for normal brain formation. Perturbation of signaling pathways involving these molecules have been shown to cause holoprosencephaly in humans and other organisms.

Introduction

Cyclopia has been known since ancient times with the descriptions of mythological single-eyed creatures living on the coast of Sicily. In humans, the comparable malformation is holoprosencephaly (HPE), which has a prevalence of 1 in 10,000–20,000 livebirths and 1 in 250 during early embryogenesis, making it the most common brain anomaly in humans (reviewed in 1, 2). The primary brain malformations comprise incomplete cleavage of the forebrain (prosencephalon) into right and left hemispheres, into telencephalon and diencephalon, and into olfactory and optic bulbs and tracts. In the most severe form, a single brain ventricle is present without any evidence of an interhemispheric fissure 3, 4. The spectrum of brain malformations in HPE extends from most to least severe in unbroken continuity. These brain malformations are frequently accompanied by facial anomalies including cyclopia with a proboscis (nose-like structure) above the eye, a single-nostril nose, median cleft lip, and others [5]. Developmental delay is present in virtually all affected individuals with central nervous system anomalies, although the degree of delay is variable, correlating with the severity of the brain malformation. Likewise, survival of children with HPE depends on the severity of the central nervous system anomalies. The majority of children with severe HPE die during the first year of life [6].

Section snippets

Embryology of forebrain development

Much of what we know about the pathogenesis of HPE is derived from observations in animals. Embryologically, HPE can be traced to varying degrees of loss or disruption in the development of ventral forebrain and midline facial structures. In normal development, the optic vesicles evaginate from the lateral walls of the forebrain, at locations separated by the developing structures of the ventral forebrain. In severe HPE, ventral forebrain structures are absent and the optic primordia

Etiology of HPE

HPE is etiologically extremely heterogeneous, with both environmental and genetic bases. Its formation may depend on an interaction of both genetic and environmental factors in at least some cases. Specific teratogens such as maternal diabetes have been shown to increase the risk for HPE 200-fold. Numerous other teratogens are known to cause HPE in various animal models (see above). Evidence for genetic causes of HPE as well as for its heterogeneity comes from, first, familial occurrence of

The Sonic hedgehog pathway in brain development and HPE

The Hedgehog (Hh) signaling pathway (Figure 2) is best defined in Drosophila, where the hedgehog gene was identified and isolated but also is well conserved in many vertebrate species (for recent reviews, see 2, 7, 14). The biologically active form of the Hh class of proteins involves cleavage of a signal sequence upon entry of the Hh precursor protein into the secretory pathway, followed by an internal autocatalytic cleavage coupled with the addition of cholesterol to the 19 kD amino-terminal

ZIC2 mutations in HPE

The second HPE-associated gene, ZIC2, was identified by positional cloning in the minimal critical region of human chromosome 13q32 [30]. ZIC2 is a member of a family that includes the Drosophila gene Odd-paired and the zebrafish gene Odd-paired like which both contain zinc finger DNA binding motifs of specificity very closely related to that of the Gli proteins (reviewed in [31]). In Drosophila, the Odd-paired gene (Opa) appears to affect the expression of targets of Hedgehog signaling, and

SIX3 mutations in HPE

The third known HPE-associated gene, SIX3, which was identified by a positional candidate gene approach, is on human chromosome 2p21 [34•]. The vertebrate Six-3 genes have been shown to participate in midline forebrain and eye formation in several organisms ([35]; reviewed in [31]). Six-3 message is present in the rostral, anterior region of the neural plate, optic recess, developing retina, and midline ventral forebrain. The Sine oculis (So)/SIX family of transcription factors form a distantly

TGIF mutations in HPE

The fourth human gene known to be associated with HPE, TG-interacting factor (TGIF) resides in the HPE minimal critical region on chromosome 18p11.3 [38]. TGIF was first identified as a homeodomain protein capable of binding a retinoid-responsive motif [39]. TGIF and RXR compete for binding to the promoter element by sterically hindering binding to overlapping sequences within the RXR response element [40]. Thus, TGIF is of interest as a repressor of retinoic acid regulated gene transcription.

Conclusions

A better understanding of the underlying mechanisms of normal and abnormal brain morphogenesis has been derived mainly from the studies of various animal models. Cloning and analysis of genes in Drosophila, zebrafish, and the mouse has helped identify HPE-associated genes by a positional candidate approach. Although mutations in SHH, ZIC2, SIX3, and TGIF can result in HPE, alterations in these genes account only for a minority of both familial and sporadic instances of disease. Thus, the search

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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