Abstract
Autosomal dominant mutations in the gene encoding the basic helix-loop-helix transcription factor Twist1 are associated with limb and craniofacial defects in humans with Saethre-Chotzen syndrome. The molecular mechanism underlying these phenotypes is poorly understood. We show that ectopic expression of the related basic helix-loop-helix factor Hand2 phenocopies Twist1 loss of function in the limb and that the two factors have a gene dosage - dependent antagonistic interaction. Dimerization partner choice by Twist1 and Hand2 can be modulated by protein kinase A - and protein phosphatase 2A - regulated phosphorylation of conserved helix I residues. Notably, multiple Twist1 mutations associated with Saethre-Chotzen syndrome alter protein kinase A - mediated phosphorylation of Twist1, suggesting that misregulation of Twist1 dimerization through either stoichiometric or post-translational mechanisms underlies phenotypes of individuals with Saethre-Chotzen syndrome.
| Original language | English |
|---|---|
| Pages (from-to) | 373-381 |
| Number of pages | 8 |
| Journal | Nature Genetics |
| Volume | 37 |
| Issue number | 4 |
| Early online date | 27 Feb 2005 |
| DOIs | |
| Publication status | Published - Apr 2005 |
Bibliographical note
We thank K. Dionne and I. Messina for technical assistance; S. Weiner for help with in situ analyses; and L. Field, C. Tabin, T. Jessell, A. Kania, D. Vasiliauskas, L. Zeltser and members of the laboratory of E.L. for comments on the manuscript. This work was supported by the National Institutes of Health (to A.B.F., D.M.V. and D.K.), March of Dimes Birth Defects Foundation (to A.B.F.), American Cancer Society (to P.C.), American Heart Association (to P.C.) and Howard Hughes Medical Institute Research Resources Program for Medical Schools (to E.L.).Keywords
- BHLH TRANSCRIPTION FACTOR
- OSTEOBLAST DIFFERENTIATION
- BASIC DOMAIN
- DNA-BINDING
- CHICK LIMB
- MUTATIONS
- PROTEIN
- HEDGEHOG
- DHAND
- GENE