The bones of the skull are primarily formed by intramembranous ossification. The intervening spaces between these flat bones are the sutures, which are the growth centers for these bones. Suture fusion usually occurs 20-30 years after birth, however premature suture fusion, or craniosynostosis, is a common disorder occurring in 1 in 2500 individuals. The most common autosomal dominant disorder of craniosynostosis is Saethre-Chotzen syndrome, which is associated with null mutations within the Twist gene. Others and we have characterized Twist as a negative regulator of muscle and bone differentiation. Twist is an evolutionarily conserved basic-Helix-Loop-Helix (bHLH) transcription factor and this inhibition requires heterodimerization with ubiquitously expressed bHLH proteins termed E proteins. Recently, in Drosophila, Twist homodimers have been implicated in the promotion of mesoderm formation and muscle differentiation. Therefore, these different Twist dimers may have different functions. Based on the expression patterns of different bHLH proteins in the cranial sutures we propose that within different regions of the sutures Twist forms different dimers and hence have different functions. We have begun to test this hypothesis by creating """"""""forced"""""""" homo and heterodimers of Twist and the E protein E12 (TT and TE, respectively). We find that cells expressing TT and TE behave quite differently and their proliferative response is consistent with that of the cells in the predicted T/T and T/E domains in the sutures. Furthermore, we have identified genes that are differentially regulated by the Twist dimers and they are expressed in the predicted domains for T/T and T/E in the sutures. Several of these genes are involved in the regulation or transmittance of FGF, BMP, and TGFbeta signaling, all of which are involved in regulating suture patency. In testing our hypothesis the Specific Aims proposed here are designed to develop a better understanding of the mechanisms underlying the normal and abnormal regulation of suture patency by Twist and to further our understanding of the relationship between Twist and FGF signaling. To do this we will: identify T/T and T/E domains in the sutures of wild type and Twist +/- mice (Specific Aim 1); determine the effect of altering Twist dimer formation or expression on cranial suture fusion and calvarial cell differentiation (Specific Aim 2); and determine the role of FGF signaling in suture fusion of Twist +/- mice (Specific Aim 3).
| Connerney, Jeannette; Andreeva, Viktoria; Leshem, Yael et al. (2008) Twist1 homodimers enhance FGF responsiveness of the cranial sutures and promote suture closure. Dev Biol 318:323-34 |
| Connerney, Jeannette; Andreeva, Viktoria; Leshem, Yael et al. (2006) Twist1 dimer selection regulates cranial suture patterning and fusion. Dev Dyn 235:1345-57 |
