THE SHH SIGNALING PATHWAY IN TOOTH DEVELOPMENT - DEFECTS IN GLI2 AND GLI3 MUTANTS

The expression of genes involved in the Sonic Hedgehog signalling path way, including Shh, Ptc, Smo, Gli1, GEi2 and Gli3, were found to be ex pressed in temporal and spatial patterns during early murine tooth dev elopment, suggestive of a role in early tooth germ initiation and subs equent epithelial-mesenchymal interactions, Of these Ptc, Smo, Gli1, G li2 and Gli3 were expressed in epithelium and mesenchyme whereas Shh w as only detected in epithelium. This suggests that Shh is involved in both lateral (epithelial-mesenchymal) and planar (epithelial-epithelia l) signalling in early tooth development, Ectopic application of Shh p rotein to mandibular mesenchyme induced the expression of Ptc and Gli1 . Addition of exogenous Shh protein directly into early tooth germs an d adjacent to tooth germs, resulted in abnormal epithelial imagination , indicative of a role for Shh in epithelial cell proliferation. In or der to assess the possible role of this pathway, tooth development in Gli2 and Gli3 mutant embryos was investigated. Gli2 mutants were found to have abnormal development of maxillary incisors, probably resultin g from a mild holoprosencephaly, whereas Gli3 mutants had no major too th abnormalities, Gli2/Gli3 double homozygous mutants did not develop any normal teeth and did not survive beyond embryonic day 14.5; howeve r, Cli2(-/-); Gli3(+/-) did survive until birth and had small molars a nd mandibular incisors whereas maxillary incisor development was arres ted as a rudimentary epithelial thickening. These results show an esse ntial role for Shh signalling in tooth development that involves funct ional redundancy of downstream GEi genes.