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

Abstract

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.

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Hhinteracting protein (HIP) can compete with PTC in Hh binding to inhibit Hh signaling (Chuang and McMahon, 1999). Additional molecules, Ihog (or its vertebrate homologs CDO and BOC), GAS1 and Glypican-3, are also able to bind Hh (Okada et al, 2006;Tenzen et al, 2006;Yao et al, 2006;Zhang et al, 2006;Allen et al, 2007;Martinelli and Fan, 2007;Seppala et al, 2007;Capurro et al, 2008) although the Hh-Ihog binding mode is very different from Shh-CDO interaction (McLellan et al, 2008). It is still not entirely clear how binding of Hh proteins results in the pathway activation.…”

The Role of Gas1 in Embryonic Development and its Implications for Human Disease

“…To address this issue, compound mutants between Gas1 and Shh were generated to test for a potential genetic interaction, and we discovered that Gas1 is a bona fide genetic modifier of Shh in the multiple developmental systems examined, including the craniofacial structure, heart, spinal cord, somite and limb. 30,33 Using a battery of cell type-specific molecular markers as readouts for HH signaling in these compound mutants, 30,31 it was found that from the genotypes of Gas1 -/-, Gas1 -/-;Shh +/-, Shh -/-, to Gas1 -/-;Shh -/-, there is a progressive reduction in HH signaling (relative to wild type and Gas1 +/-;Shh +/-controls). These data indicate that, contrary to the original expectations, Gas1 acts positively rather than negatively in HH signaling.…”

“…52 Gas1 or Cdo single mutant mice have microform holoprocencephaly, a phenotype that is further exacerbated in the Shh +/-background. 30,31,33,[40][41][42] Are Gas1 and Cdo modifier loci that contribute to the large spectrum of holoprosencephaly in humans? Conversely, increased SHH signaling, either by reducing PTC1 activity or increasing SHH, SMO, or GLI activities, leads to several types of tumors such as basal cell carcinoma, medullablastoma and prostate cancer.…”

Effects of Gas1 on gliomas: a review on current preclinical studies

“…mice die immediately after birth. [89][90][91] The K.O. mice develop several defects including decreased cell proliferation in cerebellum, morphological alterations in the gastrointestinal tract and microform holoprosencephaly associated with multiple craniofacial defects.…”

“…mice develop several defects including decreased cell proliferation in cerebellum, morphological alterations in the gastrointestinal tract and microform holoprosencephaly associated with multiple craniofacial defects. [72,[89][90][91][92][93] The defects in Gas1-/-mice, are associated with the loss of the signaling induced by Sonic hedgehog (Shh). Interestingly, some patients with holoproscencephaly present mutations in the Gas1 gene with or without additional mutations on the Shh gene.…”