Hedgehog signalling regulates patterning of the murine and human dentitions through Gas1 co-receptor function

The mammalian dentition exhibits wide numerical and morphological variation between different species. The regulation of dental pattern is achieved through complex reiterative molecular signalling interactions that occur through multiple stages of tooth development. We show that mice with loss-of-function in the Hedgehog co-receptor Gas1 have variation in size, morphology and number of teeth within the molar dentition. Specifically, premolar-like supernumerary teeth are present with high penetrance, arising through survival and continued development of vestigial tooth germs. We further demonstrate that Gas1 function in cranial neural crest cells is essential for the regulation of tooth number, acting to restrict Wnt signalling in vestigial tooth germs through facilitation of Shh signalling. Moreover, regulation of tooth number is independent of the additional Hedgehog co-receptors Cdon and Boc. Interestingly, further reduction of Shh pathway activity in a Gas1 mutant background leads to fusion of the molar field and ultimately, developmental arrest of tooth development rather than exacerbating the supernumerary phenotype. Finally, we demonstrate defective coronal morphology in the molar dentition of human subjects carrying GAS1 missense mutations, suggesting that regulation of Hedgehog signalling through GAS1 is also essential for normal patterning of the human dentition.