Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog
Maisa Seppala, … , Paul T. Sharpe, Martyn T. Cobourne
Maisa Seppala, … , Paul T. Sharpe, Martyn T. Cobourne
Published June 1, 2007
Citation Information: J Clin Invest. 2007;117(6):1575-1584. https://doi.org/10.1172/JCI32032.
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Research Article Development

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.

Authors

Maisa Seppala, Michael J. Depew, David C. Martinelli, Chen-Ming Fan, Paul T. Sharpe, Martyn T. Cobourne

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Figure 4

Palatogenesis in WT and Gas1–/– mice.

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Palatogenesis in WT and Gas1–/– mice. (A and B) Scanning...
(A and B) Scanning electron microscopy demonstrating that palate development was complete in WT mice at P0 (A), while there was a full-penetrance cleft of the secondary palate in affected Gas1–/– mice at the same time point (B). (C and D) Histological analysis showed comparable morphology of the palatal shelves at E13.5 in WT and Gas1–/– embryos. (E and F) At E15.5, while the shelves rose above the tongue and fused in the midline in the WT embryos, fusion failed to occur in affected Gas1–/– embryos. Scale bar: 1.25 mm (A and B); 500 μm (C–F).