Control of cranial ectomesenchyme fate by Nr2f nuclear receptors

Certain cranial neural crest cells are uniquely endowed with the ability to make skeletal cell types otherwise only derived from mesoderm. As these cells migrate into the pharyngeal arches, they downregulate neural crest specifier genes and upregulate so-called ectomesenchyme genes that are characteristic of skeletal progenitors. Although both external and intrinsic factors have been proposed as triggers of this transition, the details remain obscure. Here, we report the Nr2f nuclear receptors as intrinsic activators of the ectomesenchyme program: zebrafish nr2f5 single and nr2f2;nr2f5 double mutants show marked delays in upregulation of ectomesenchyme genes, such as dlx2a, prrx1a, prrx1b, sox9a, twist1a and fli1a, and in downregulation of sox10, which is normally restricted to early neural crest and non-ectomesenchyme lineages. Mutation of sox10 fully rescued skeletal development in nr2f5 single but not nr2f2;nr2f5 double mutants, but the initial ectomesenchyme delay persisted in both. Sox10 perdurance thus antagonizes the recovery but does not explain the impaired ectomesenchyme transition. Unraveling the mechanisms of Nr2f function will help solve the enduring puzzle of how cranial neural crest cells transition to the skeletal progenitor state.