Twist1 homodimers enhance FGF responsiveness of the cranial sutures and promote suture closure.
Haploinsufficiency of the transcription factor TWIST1 is associated with Saethre-Chotzen Syndrome and is manifested by craniosynostosis, which is the premature closure of the calvaria sutures. Previously, we found that Twist1 forms functional homodimers and heterodimers that have opposing activities. Our data supported a model that within the calvaria sutures Twist1 homodimers (T/T) reside in the osteogenic fronts while Twist1/E protein heterodimers (T/E) are in the mid-sutures. Twist1 haploinsufficiency alters the balance between these dimers, favoring an increase in homodimer formation throughout the sutures. The data we present here further supports this model and extends it to integrate the Twist1 dimers with the pathways that are known to regulate cranial suture patency. This data provides the first evidence of a functional link between Twist1 and the FGF pathway, and indicates that differential regulation of FGF signaling by T/T and T/E dimers plays a central role in governing cranial suture patency. Furthermore, we show that inhibition of FGF signaling prevents craniosynostosis in Twist1(+/-) mice, demonstrating that inhibition of a signaling pathway that is not part of the initiating mutation can prevent suture fusion in a relevant genetic model of craniosynostosis.
Connerney
Jeannette
J
Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074, USA.
Andreeva
Viktoria
V
Leshem
Yael
Y
Mercado
Miguel A
MA
Dowell
Karen
K
Yang
Xuehei
X
Lindner
Volkhard
V
Friesel
Robert E
RE
Spicer
Douglas B
DB
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation; D003393:Cranial Sutures / Q000378:metabolism*; D003398:Craniosynostoses / Q000378:metabolism; D019281:Dimerization; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D051879:Twist-Related Protein 1 / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; D009687:Nuclear Proteins; D017468:Receptors, Fibroblast Growth Factor; D051879:Twist-Related Protein 1; D016222:Fibroblast Growth Factor 2; C067250:Twist1 protein, mouse; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2