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EMBO reports 9, 10, 1041–1047 (2008)
doi:10.1038/embor.2008.161
AOP Published online: 22 August 2008
HAND transcription factors are required for neonatal sympathetic neuron survival
Epaminondas Doxakis1, 2, Laura Howard2, Hermann Rohrer3 & Alun M Davies2
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1 Basic Neurosciences Division, Biomedical Research Foundation of the Academy of Athens, Soranou Efesiou 4, Athens, Greece
2 School of Biosciences, Museum Avenue, Cardiff CF10 3US, UK
3 Department of Neurochemistry, Max-Planck-Institut fuer Hirnforschung, FG Entwicklungsneurobiologie, Deutschordenstrasse 46, 60528 Frankfurt/Main, Germany
To whom correspondence should be addressed
Alun M Davies Tel: +44 (0)2920 874303; Fax: +44 (0)2920 874116; E-mail: daviesalun@cf.ac.uk
Received 4 December 2007; Accepted 9 July 2008; Published online 22 August 2008.
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Abstract
Expression of the basic helix–loop–helix transcription factor HAND2 begins early in sympathetic neuron development and is essential for the differentiation of noradrenergic neurons. Here, we show that the expression of HAND2 and related HAND1 are maintained in sympathetic neurons throughout fetal and postnatal development when these neurons depend on target-derived nerve growth factor (NGF) for survival. Short interfering RNA knockdown of endogenous HAND2 and, to a lesser extent, HAND1 in neonatal sympathetic neurons cultured with NGF, reduced the expression of the NGF receptor tyrosine kinase TrkA (tropomyosin-related kinase A), as well as neuronal survival. Chromatin immunoprecipitation analysis showed that NGF promotes HAND2 binding to the TrkA minimal enhancer and that transfection of sympathetic neurons with a TrkA expression plasmid rescued the neurons from HAND knockdown. These findings show that HAND transcription factors have a crucial function in sustaining the survival of neonatal sympathetic neurons with NGF by a feed-forward loop that maintains the expression of TrkA.
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