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Twist1 dimer selection regulates cranial suture patterning and fusion.
Dev Dyn 2006; 235(5):1345-57DD

Abstract

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.

Authors+Show Affiliations

Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine 04074, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16502419

Citation

Connerney, Jeannette, et al. "Twist1 Dimer Selection Regulates Cranial Suture Patterning and Fusion." Developmental Dynamics : an Official Publication of the American Association of Anatomists, vol. 235, no. 5, 2006, pp. 1345-57.
Connerney J, Andreeva V, Leshem Y, et al. Twist1 dimer selection regulates cranial suture patterning and fusion. Dev Dyn. 2006;235(5):1345-57.
Connerney, J., Andreeva, V., Leshem, Y., Muentener, C., Mercado, M. A., & Spicer, D. B. (2006). Twist1 dimer selection regulates cranial suture patterning and fusion. Developmental Dynamics : an Official Publication of the American Association of Anatomists, 235(5), pp. 1345-57.
Connerney J, et al. Twist1 Dimer Selection Regulates Cranial Suture Patterning and Fusion. Dev Dyn. 2006;235(5):1345-57. PubMed PMID: 16502419.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Twist1 dimer selection regulates cranial suture patterning and fusion. AU - Connerney,Jeannette, AU - Andreeva,Viktoria, AU - Leshem,Yael, AU - Muentener,Christian, AU - Mercado,Miguel A, AU - Spicer,Douglas B, PY - 2006/2/28/pubmed PY - 2006/12/12/medline PY - 2006/2/28/entrez SP - 1345 EP - 57 JF - Developmental dynamics : an official publication of the American Association of Anatomists JO - Dev. Dyn. VL - 235 IS - 5 N2 - 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. SN - 1058-8388 UR - https://www.unboundmedicine.com/medline/citation/16502419/Twist1_dimer_selection_regulates_cranial_suture_patterning_and_fusion_ L2 - https://doi.org/10.1002/dvdy.20717 DB - PRIME DP - Unbound Medicine ER -