Gas1 Regulates Patterning of the Murine and Human Dentitions through Sonic Hedgehog

Abstract

The mammalian dentition is a serially homogeneous structure that exhibits wide numerical and morphological variation among multiple different species. Patterning of the dentition is achieved through complex reiterative molecular signaling interactions that occur throughout the process of odontogenesis. The secreted signaling molecule Sonic hedgehog (Shh) plays a key role in this process, and the Shh coreceptor growth arrest-specific 1 (Gas1) is expressed in odontogenic mesenchyme and epithelium during multiple stages of tooth development. We show that mice engineered with Gas1 loss-of-function mutation have variation in number, morphology, and size of teeth within their molar dentition. Specifically, supernumerary teeth with variable morphology are present mesial to the first molar with high penetrance, while molar teeth are characterized by the presence of both additional and absent cusps, combined with reduced dimensions and exacerbated by the presence of a supernumerary tooth. We demonstrate that the supernumerary tooth in Gas1 mutant mice arises through proliferation and survival of vestigial tooth germs and that Gas1 function in cranial neural crest cells is essential for the regulation of tooth number, acting to restrict Wnt and downstream FGF signaling in odontogenic epithelium through facilitation of Shh signal transduction. Moreover, regulation of tooth number is independent of the additional Hedgehog coreceptors Cdon and Boc, which are also expressed in multiple regions of the developing tooth germ. Interestingly, further reduction of Hedgehog pathway activity in Shhtm6Amc hypomorphic mice leads to fusion of the molar field and reduced prevalence of supernumerary teeth in a Gas1 mutant background. Finally, we demonstrate defective coronal morphology and reduced coronal dimensions in the molar dentition of human subjects identified with pathogenic mutations in GAS1 and SHH/GAS1, suggesting that regulation of Hedgehog signaling through GAS1 is also essential for normal patterning of the human dentition.

Roles of circular RNAs in osteogenic differentiation of bone marrow mesenchymal stem cells (Review)

“…Differentially expressed circRNAs were found in elderly patients with OP, and through further experiments, it was found that circRNA008876 can play a biological role as an miR-150-5p sponge ( 49 ), which provides a potential biomarker and therapeutic target for senile OP. A previous study showed that Shh coreceptor growth arrest-specific 1 (GAS1) is expressed in mesenchymal cells, and in a GAS1-deficient mouse model, mice have abnormal dentition ( 50 ). Another study has also shown that inhibiting the expression of circ_0003865 in patients with OP can promote the osteogenic differentiation of BMSCs, and that circ_0003865 regulates the expression of the GAS1 gene by sponging miR-3653-3p ( 51 ).…”

Elevated WNT signaling and compromised Hedgehog signaling due to Evc2 loss of function contribute to the abnormal molar patterning

“…Previous studies have indicated that elevated WNT signaling and decreased Hedgehog signaling leads to abnormal molar patterning and supernumerary tooth formation in mice ( 37 , 38 ). We therefore investigated WNT signaling changes in E16.5 Evc2 global mutant molars using LEF1 as a readout of active WNT signaling.…”

Hedgehog-dependent and Hedgehog-independent roles for Growth Arrest Specific 1 in mammalian kidney morphogenesis

“…Our data indicate that GAS1 can be secreted in the metanephros, therefore the requirements for GAS1 in a specific pathway (e.g., HH versus RET) could depend on whether it is acting in a cell-autonomous manner (i.e., membrane-tethered) or in a non-cell autonomous fashion (i.e., secreted). GAS1 may also act on multiple signaling pathways simultaneously in a single tissue during development, as suggested for gut development, forebrain development and dentition patterning (Biau et al, 2013; Marczenke et al, 2021; Seppala et al, 2022).…”