Characterization of a neurotrophin signaling mechanism that mediates neuron survival in a temporally specific pattern.
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.
Shalizi
Aryaman
A
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Lehtinen
Maria
M
Gaudilliere
Brice
B
Donovan
Nicole
N
Han
Jiahuai
J
Konishi
Yoshiyuki
Y
Bonni
Azad
A
D000367:Age Factors; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000166:cytology / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D007700:Kinetics; D020935:MAP Kinase Signaling System; D064326:MEF2 Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018006:Myogenic Regulatory Factors; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D020933:Neurotrophin 3 / Q000235:genetics; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D020933:Neurotrophin 3; D014157:Transcription Factors; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases