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Published online 18 October 2004. doi:10.1083/jcb.200406131
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 2, 257-267
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Article

 Interaction of Brn3a and HIPK2 mediates transcriptional repression of sensory neuron survival

Amanda K. Wiggins1,4, Guangwei Wei1,4, Epaminondas Doxakis5, Connie Wong1,4, Amy A. Tang1,4, Keling Zang2,3, Esther J. Luo1,4, Rachael L. Neve6, Louis F. Reichardt2,3, and Eric J. Huang1,4

1 Department of Pathology, University of California San Francisco, San Francisco, CA 94143
2 Department Physiology, University of California San Francisco, San Francisco, CA 94143
3 Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94143
4 Veterans Affairs Medical Center, San Francisco, CA 94121
5 Department of Preclinical Sciences, Royal (Dick) School of Veterinary Studies, Edinburgh EH9 12H, UK
6 Department of Psychiatry, Harvard Medical School, Belmont, MA 02478

Address correspondence to Eric J. Huang: ejhuang{at}itsa.ucsf.edu

The Pit1-Oct1-Unc86 domain (POU domain) transcription factor Brn3a controls sensory neuron survival by regulating the expression of Trk receptors and members of the Bcl-2 family. Loss of Brn3a leads to a dramatic increase in apoptosis and severe loss of neurons in sensory ganglia. Although recent evidence suggests that Brn3a-mediated transcription can be modified by additional cofactors, the exact mechanisms are not known. Here, we report that homeodomain interacting protein kinase 2 (HIPK2) is a pro-apoptotic transcriptional cofactor that suppresses Brn3a-mediated gene expression. HIPK2 interacts with Brn3a, promotes Brn3a binding to DNA, but suppresses Brn3a-dependent transcription of brn3a, trkA, and bcl-xL. Overexpression of HIPK2 induces apoptosis in cultured sensory neurons. Conversely, targeted deletion of HIPK2 leads to increased expression of Brn3a, TrkA, and Bcl-xL, reduced apoptosis and increases in neuron numbers in the trigeminal ganglion. Together, these data indicate that HIPK2, through regulation of Brn3a-dependent gene expression, is a critical component in the transcriptional machinery that controls sensory neuron survival.

A.K. Wiggins and G. Wei contributed equally to this work.

Abbreviations used in this paper: EGFP-HIPK2, EGFP-tagged HIPK2; ES, embryonic stem; HDAC, histone deacetylase; HIPK2, homeodomain interacting protein kinase 2; HSV, herpes simplex virus; LacZ, ß-galactosidase; MEF, mouse embryonic fibroblast; MOI, multiplicity of infection; POU domain, Pit1-Oct1-Unc86 domain; qRT-PCR, quantitative RT-PCR.


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