The basic helix-loop-helix factor Hand 2 regulates autonomic nervous system development.

Mammalian autonomic nervous system (ANS) development requires the combinatorial action of a number of transcription factors, which include Mash 1, Phox 2b, and GATA 3. Here we show that the bHLH transcription factor, Hand 2 (dHAND), is expressed concurrently with Mash 1 during sympathetic nervous system (SNS) development and that the expression of Hand 2 is not dependent on Mash 1. This suggests that these two bHLH factors work in parallel during SNS development. We also show that ectopic expression of Hand 2 activates the neuronal program and promotes the acquisition of a phenotype corresponding to peripheral neurons including neurons of the SNS lineage in P19 embryonic carcinoma cells. We propose that Hand 2 works in parallel with other members of the transcriptional network to regulate ANS developmental but can ectopically activate the program by a cross-regulatory mechanism that includes the activation of Mash 1. We show that this function is dependent on its interaction with the histone acetyltransferase p300/CBP, indicating that Hand 2 functions to promote ANS development as part of a larger transcriptional complex.