The present study was performed to determine if coding errors in Gli3, Ihh, Rab23, or Jag1 could be causally linked to craniosynostosis in this unique animal model.
A single patient with acrocallosal syndrome and a de novo p.Ala934Pro mutation in GLI3 has been reported, whereas diverse and numerous GLI3 mutations have also been described in syndromes with overlapping clinical manifestations, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, trigonocephaly with craniosynostosis and polydactyly, oral-facial-digital syndrome, and non-syndromic polydactyly.
Gli3(Xt-J/Xt-J) Runx2(+/-) mice have neither craniosynostosis nor additional ossification centers in interfrontal suture and displayed a normalization of Dlx5, Runx2-II, and pSmad1/5/8 expression as well as sutural mesenchymal cell proliferation.
Taken together, we define a novel role for Gli3 in osteoblast development; we describe the first mouse model of lambdoid suture craniosynostosis and show how craniosynostosis can be rescued in this model.
The most common genetic mutations identified in syndromic craniosynostosis involve the fibroblast growth factor receptor (FGFR) family with other mutations occurring in genes for transcription factors TWIST, MSX2, and GLI3, and other proteins EFNB1, RAB23, RECQL4, and POR, presumed to be involved either upstream or downstream of the FGFR signaling pathway.