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The Journal of Neuroscience, August 13, 2003, 23(19):7326-7336

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Characterization of a Neurotrophin Signaling Mechanism that Mediates Neuron Survival in a Temporally Specific Pattern

Aryaman Shalizi,^1,2 Maria Lehtinen,^1,3 Brice Gaudillière,^1,2 Nicole Donovan,¹ Jiahuai Han,⁴ Yoshiyuki Konishi,¹ and Azad Bonni^1,2,3

¹Department of Pathology and Programs in ²Biological and Biomedical Sciences and ³Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, and ⁴Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

The temporally specific nature of neurotrophic factor-induced responses is a general feature of mammalian nervous system development, the mechanisms of which remain to be elucidated. We characterized a mechanism underlying the temporal specificity by which BDNF selectively promotes the survival of newly generated, but not mature, granule neurons of the mammalian cerebellum. We found that BDNF specifically induces the extracellular signal-regulated kinase 5 (ERK5)-myocyte enhancer factor (MEF2) signaling pathway in newly generated granule neurons and thereby induces transcription of neurotrophin-3 (NT-3), a novel gene target of MEF2. Inhibition of endogenous ERK5, MEF2, or NT-3 in neurons by several approaches including disruption of the NT-3 gene in mice revealed a requirement for the ERK5-MEF2-NT-3 signaling pathway in BDNF-induced survival of newly generated granule neurons. These findings define a novel mechanism that underlies the antiapoptotic effect of neurotrophins in a temporally defined pattern in the developing mammalian brain.

Key words: BDNF; ERK5; MEF2; CREB; NT-3; neuron; apoptosis; survival; transcription

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Received Mar. 4, 2003; revised May. 5, 2003; accepted May. 13, 2003.

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