Transcriptional Regulation of Autonomic Neuron Development

The autonomic nervous system is derived from the neural crest, a transient embryonic progenitor population of stem-like cells. Neural crest cells give rise to a diverse array of approximately 23 derivatives including bone, melanocytes and neurons. This cellular diversity led us to ask what mechanisms, both cell extrinsic and intrinsic, might contribute to fate determination, phenotype selection and cell type-specific gene expression. We identified the basic helix-loop-helix DNA binding protein Hand2 as a transcriptional regulator with essential functions for the development of sympathetic and enteric neurons with no apparent function for development of either parasympathetic or sensory neurons. For sympathetic ganglion neurons, Hand2 functions in a network of transcriptional regulators, which includes the homeodomain DNA binding protein Phox2b, the bHLH DNA binding protein Ascl1, the zinc-finger proteins Gata3 and INSM1. Hand2 controls expression of these other proteins and which together regulate differentiation and cell type-specific gene expression. Loss of Hand2 function is embryonic lethal due to lack of norepinephrine secreting neurons; Hand2 regulates cell proliferation, expression of β-tubulin, Hu, tyrosine hydroxylase and function of dopamine-β-hydroxylase, linking neurogenesis and cell type-specific gene expression of sympathetic ganglion neurons. Interestingly, in the enteric nervous system, in addition to regulating proliferation of neural crest-derived enteric neural precursors, Hand2 regulates expression of a subset of neurotransmitters/neuromodulators as well as overall pattering of the enteric nervous system. We have identified Hand2 target genes that mediate a number of Hand2 functions in both the sympathetic and enteric nervous systems. In total, these results suggest that Hand2 is a multifunctional transcriptional regulator essential for aspects of sympathetic and enteric neuron development.