A retrograde neuronal survival response: target-derived neurotrophins regulate MEF2D and bcl-w.
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.
Pazyra-Murphy
Maria F
MF
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Hans
Aymeric
A
Courchesne
Stephanie L
SL
Karch
Christoph
C
Cosker
Katharina E
KE
Heerssen
Heather M
HM
Watson
Fiona L
FL
Kim
Taekyung
T
Greenberg
Michael E
ME
Segal
Rosalind A
RA
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D020287:In Situ Nick-End Labeling / Q000379:methods; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014162:Transfection / Q000379:methods
D004791:Enzyme Inhibitors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; D048054:Mitogen-Activated Protein Kinase 7; C447615:PTPN9 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor