Growth arrest-specific gene 1 (Gas1) encodes a GPI-linked membrane glycoprotein that has been shown to act as an inhibitor of Sonic hedgehog (Shh) signalling. Shh plays a critical role during craniofacial development. Loss of Shh signalling in mice and humans can lead to holoprosencephaly, a congenital disorder characterized by failure of the embryonic forebrain to subdivide into two telencephalic vesicles and defects in midline development of the face. It also plays an important role in palatal and tooth development.
Objectives and Methods:
Objective of this study was to analyse the craniofacial phenotype of Gas1-/- mice and investigate possible genetic interactions between Gas1 and Shh through generation Gas1-/-Shh+/- mutant mice.
Results:
Anomalies found in Gas1-/- mice predominantly affect the craniofacial midline including cleft palate, premaxillary hypoplasia, single maxillary incisors and pituitary gland malformations. They also have premolar-like supernumerary teeth. Molecular investigation and genetic analysis by utilizing Gas1/Shh mice provided convincing evidence that these molecules positively interact: the loss of a single Shh allele in a Gas1 mutant background produced a more severe defect of the facial midline. Interestingly, they also display a mirror image of the proximal mandible including a presence of ectopic tooth formation.
Conclusions:
Midline defects seen in Gas1 mutant mice are characteristic of mild holoprosencephaly, the most common structural anomaly of the human brain (1:250 embryos, 1:10,000-20,000 births). This study represents GAS1 as a candidate modifier gene for this condition and prompts speculation that Gas1 might, contradictory to its previously known role, facilitate long-range shh signalling. However, presence of supernumerary teeth is suggestive of abundant Shh signalling and Gas1 might differentially regulate Shh signalling in the first branchial arch derivatives in comparison to other facial structures.
Funded by a European Union Early Stage Marie Curie Fellowship, Contract No MEST-CT-2004-50402