S06-02 Neural crest and outflow tract development

The homeodomain factor Nkx2-5 is expressed in cardiac progenitor cells of the first and second heart fields, and in differentiating cardiomyocytes and conduction cells. NKX2-5 mutations cause congenital heart disease (CHD) and conduction disease (CD) in humans. Nkx2-5 acts as both a repressor and an activator, and one of its early roles is to repress, through a negative feedback loop, the expression of the Bmp2 gene, which encodes one of the upstream inducers of cardiogenesis and is itself a repressor of cardiac progenitor cell proliferation. In this way Nkx2-5 orchestrates a transition between a period of cardiac induction and one of heart progenitor cell expansion and deployment. We have also studied the Nkx2-5 transcriptional cofactor, Tbx20, a member of the T-box transcription factor family, and shown that Tbx20 mutations also cause CHD as well as adult-onset dilated cardiomyopathy (DCM). The T-box DNA binding domain of Tbx20 has unique biophysical properties, with its tertiary hydrophobic interactions existing in a state of dynamic equilibrium akin to a molten globule, a state that may facilitate formation and/or stability of transcriptional complexes. Gain-of-function mutations can exacerbate this state. These studies address CHD at the molecular, cellular and organ level and contribute to an understanding of CHD origins and patient management.