Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog

Carnegie Institute, Baltimore, Maryland, United States
Journal of Clinical Investigation (Impact Factor: 13.22). 07/2007; 117(6):1575-84. DOI: 10.1172/JCI32032
Source: PubMed


Holoprosencephaly (HPE) is a clinically heterogeneous developmental anomaly affecting the CNS and face, in which the embryonic forebrain fails to divide into distinct halves. Numerous genetic loci and environmental factors are implicated in HPE, but mutation in the sonic hedgehog (Shh) gene is an established cause in both humans and mice. As growth arrest-specific 1 (Gas1) encodes a membrane glycoprotein previously identified as a Shh antagonist in the somite, we analyzed the craniofacial phenotype of mice harboring a targeted Gas1 deletion. Gas1(-/-) mice exhibited microform HPE, including midfacial hypoplasia, premaxillary incisor fusion, and cleft palate, in addition to severe ear defects; however, gross integrity of the forebrain remained intact. These defects were associated with partial loss of Shh signaling in cells at a distance from the source of transcription, suggesting that Gas1 can potentiate hedgehog signaling in the early face. Loss of a single Shh allele in a Gas1(-/-) background significantly exacerbated the midline craniofacial phenotype, providing genetic evidence that Shh and Gas1 interact. As human GAS1 maps to chromosome 9q21.3-q22, a region previously associated with nonsyndromic cleft palate and congenital deafness, our results establish GAS1 as a potential locus for several human craniofacial malformations.

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Available from: Chen Ming Fan
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    • "These HPE microforms display subtle differences in both their features and penetrance. On a 129sv/C57BL/6 background, Cdon−/− mice have numerous anomalies associated with the premaxilla, whilst in Gas1−/− mice this region is less affected, but there is a higher incidence of cleft palate (Cole and Krauss, 2003; Seppala et al., 2007). The severity of HPE does increase with the loss of combined alleles; Gas1−/−; Cdon−/− mutants have a severe form of alobar HPE, which includes fusion of the nasal processes and absence of maxillary and mandibular skeletal elements (Fig. 3M–O) (Allen et al., 2007), whilst Cdon−/−; Boc−/− mice on a Cdon-resistant background have lobar HPE with more severe craniofacial abnormalities (Zhang et al., 2011). "
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    ABSTRACT: Holoprosencephaly is a heterogeneous developmental malformation of the central nervous system characterized by impaired forebrain cleavage, midline facial anomalies and wide phenotypic variation. Indeed, microforms represent the mildest manifestation, associated with facial anomalies but an intact central nervous system. In many cases, perturbations in sonic hedgehog signaling are responsible for holoprosencephaly. Here, we have elucidated the contribution of Gas1 and an additional hedgehog co-receptor, Boc during early development of the craniofacial midline, by generating single and compound mutant mice. Significantly, we find Boc has an essential role in the etiology of a unique form of lobar holoprosencephaly that only occurs in conjunction with combined loss of Gas1. Whilst Gas1(-/-) mice have microform holoprosencephaly characterized by a single median maxillary central incisor, cleft palate and pituitary anomalies, Boc(-/-) mice have a normal facial midline. However, Gas1(-/-); Boc(-/-) mutants have lobar holoprosencephaly associated with clefting of the lip, palate and tongue, secondary to reduced sonic hedgehog transduction in the central nervous system and face. Moreover, maxillary incisor development is severely disrupted in these mice, arresting prior to cellular differentiation as a result of apoptosis in the odontogenic epithelium. Thus, Boc and Gas1 retain an essential function in these tooth germs, independent of their role in midline development of the central nervous system and face. Collectively, this phenotype demonstrates both redundancy and individual requirements for Gas1 and Boc during sonic hedgehog transduction in the craniofacial midline and suggests BOC as a potential digenic locus for lobar holoprosencephaly in human populations.
    Full-text · Article · Jul 2014 · Biology Open
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    • "Microform holoprosencephaly, including midface hypoplasia, cleft palate, and maxillary incisor fusion [16] Tg737 orpk Premolar mesial to first molar Kidney and pancreatic cysts, preaxial polydactyly [17] "
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    ABSTRACT: Tooth development is initiated with placode formation followed by thickening of the oral ectoderm-derived dental epithelium. The dental epithelium then undergoes invagination into the dental mesenchyme, which is derived from the cranial neural crest. The subsequent reciprocal interactions between the dental epithelium and mesenchyme, involving a variety of molecules, are important for tooth morphogenesis, as well as for regulation of tooth number. Recent analyses of mouse mutants have provided important insights into the mechanisms underlying tooth development, including supernumerary tooth formation. In this review, we have discussed the molecular basis for the regulation of tooth number and supernumerary tooth formation.
    Full-text · Article · Nov 2013 · Journal of Oral Biosciences
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    • "This interaction was originally interpreted as antagonistic, but more recent work indicates this to be a cooperative effect between these two molecules (Lee, Buttitta, and Fan 2001; Allen, Tenzen, and McMahon 2007; Martinelli and Fan 2007; Allen et al. 2011; Izzi et al. 2011). Alterations in this interaction have been associated with developmental abnormalities, such as craniofacial malformations in rodents (Seppala et al. 2007) and holoprosencephaly in humans (Martinelli and Fan 2009; Ribeiro et al. 2010). It is interesting that we have also observed that GAS1 is capable of inducing cell arrest and apoptosis of human gliomas, in the absence of SHH (Dominguez-Monzon et al. 2009). "
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    ABSTRACT: Growth arrest specific 1 (GAS1) is a pleiotropic protein that induces apoptosis and cell arrest in different tumors, but it is also involved in the development of the nervous system and other tissues and organs. This dual ability is likely caused by its capacity to interact both by inhibiting the intracellular signaling cascade induced by glial cell-line derived neurotrophic factor and by facilitating the activity of the sonic hedgehog pathway. The presence of GAS1 mRNA has been described in adult mouse brain, and here we corroborated this observation. We then proceeded to determine the distribution of the protein in the adult central nervous system (CNS). We detected, by western blot analysis, expression of GAS1 in olfactory bulb, caudate-putamen, cerebral cortex, hippocampus, mesencephalon, medulla oblongata, cerebellum, and cervical spinal cord. To more carefully map the expression of GAS1, we performed double-label immunohistochemistry and noticed expression of GAS1 in neurons in all brain areas examined. We also observed expression of GAS1 in astroglial cells, albeit the pattern of expression was more restricted than that seen in neurons. Briefly, in the present article, we report the widespread distribution and cellular localization of the GAS1 native protein in adult mammalian CNS.
    Full-text · Article · Jun 2013 · Journal of Histochemistry and Cytochemistry
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