Drs. Connerney, Andreeva, and Leshem contributed equally to this work.
Twist1 dimer selection regulates cranial suture patterning and fusion
Version of Record online: 24 FEB 2006
Copyright © 2006 Wiley-Liss, Inc.
Special Issue: Craniofacial Development Special Issue
Volume 235, Issue 5, pages 1334–1346, May 2006
How to Cite
Connerney, J., Andreeva, V., Leshem, Y., Muentener, C., Mercado, M. A. and Spicer, D. B. (2006), Twist1 dimer selection regulates cranial suture patterning and fusion. Dev. Dyn., 235: 1334–1346. doi: 10.1002/dvdy.20717
- Issue online: 19 APR 2006
- Version of Record online: 24 FEB 2006
- Manuscript Accepted: 16 JAN 2006
- NIH/NIDCR/NCRR. Grant Numbers: P20 RR15555, R01 DE015329
- American Heart Association. Grant Number: 0130393
Vol. 241, Issue 2, 433, Version of Record online: 16 DEC 2011
- gene expression;
- Saethre-Chotzen syndrome;
- craniofacial development
Saethre-Chotzen syndrome is associated with haploinsufficiency of the basic-helix–loop–helix (bHLH) transcription factor TWIST1 and is characterized by premature closure of the cranial sutures, termed craniosynostosis; however, the mechanisms underlying this defect are unclear. Twist1 has been shown to play both positive and negative roles in mesenchymal specification and differentiation, and here we show that the activity of Twist1 is dependent on its dimer partner. Twist1 forms both homodimers (T/T) and heterodimers with E2A E proteins (T/E) and the relative level of Twist1 to the HLH inhibitor Id proteins determines which dimer forms. On the basis of the expression patterns of Twist1 and Id1 within the cranial sutures, we hypothesized that Twist1 forms homodimers in the osteogenic fronts and T/E heterodimers in the mid-sutures. In support of this hypothesis, we have found that genes regulated by T/T homodimers, such as FGFR2 and periostin, are expressed in the osteogenic fronts, whereas genes regulated by T/E heterodimers, such as thrombospondin-1, are expressed in the mid-sutures. The ratio between these dimers is altered in the sutures of Twist1+/− mice, favoring an increase in homodimers and an expansion of the osteogenic fronts. Of interest, the T/T to T/E ratio is greater in the coronal versus the sagittal suture, and this finding may contribute to making the coronal suture more susceptible to fusion due to TWIST haploinsufficiency. Importantly, we were able to inhibit suture fusion in Twist1+/− mice by modulating the balance between these dimers toward T/E formation, by either increasing the expression of E2A E12 or by decreasing Id expression. Therefore, we have identified dimer partner selection as an important mediator of Twist1 function and provide a mechanistic understanding of craniosynostosis due to TWIST haploinsufficiency. Developmental Dynamics 235:1345–1357, 2006. © 2006 Wiley-Liss, Inc.