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The Journal of Neuroscience, May 20, 2009, 29(20):6700-6709; doi:10.1523/JNEUROSCI.0233-09.2009

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Cellular/Molecular
A Retrograde Neuronal Survival Response: Target-Derived Neurotrophins Regulate MEF2D and bcl-w

Maria F. Pazyra-Murphy,^1,2,3 * Aymeric Hans,^1,2,3 * Stephanie L. Courchesne,^1,2,3 Christoph Karch,^1,2,3 Katharina E. Cosker,^1,2,3 Heather M. Heerssen,^1,2,3 Fiona L. Watson,^1,4 Taekyung Kim,⁵ Michael E. Greenberg,⁵ and Rosalind A. Segal^1,2,3

¹Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, ²Departments of Cancer Biology and ³Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, ⁴Department of Biology and Neuroscience Program, Washington and Lee University, Lexington, Virginia 24450, and ⁵Department of Neurobiology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Rosalind A. Segal, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Email: Rosalind_segal{at}dfci.harvard.edu

Survival and maturation of dorsal root ganglia sensory neurons during development depend on target-derived neurotrophins. These target-derived signals must be transmitted across long distances to alter gene expression. Here, we address the possibility that long-range retrograde signals initiated by target-derived neurotrophins activate a specialized transcriptional program. The transcription factor MEF2D is expressed in sensory neurons; we show that expression of this factor is induced in response to target-derived neurotrophins that stimulate the distal axons. We demonstrate that MEF2D regulates expression of an anti-apoptotic bcl-2 family member, bcl-w. Expression of mef2d and bcl-w is stimulated in response to activation of a Trk-dependent ERK5/MEF2 pathway, and our data indicate that this pathway promotes sensory neuron survival. We find that mef2d and bcl-w are members of a larger set of retrograde response genes, which are preferentially induced by neurotrophin stimulation of distal axons. Thus, activation of an ERK5/MEF2D transcriptional program establishes and maintains the cellular constituents of functional sensory circuits.

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Received Jan. 15, 2009; revised Feb. 24, 2009; accepted March 11, 2009.

Correspondence should be addressed to Rosalind A. Segal, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Email: Rosalind_segal{at}dfci.harvard.edu

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