Deafferentation-induced activation of NFAT (nuclear factor of activated T-cells) in cochlear nucleus neurons during a developmental critical period: a role for NFATc4-dependent apoptosis in the CNS.
During the development and maturation of sensory neurons, afferent activity is required for normal maintenance. There exists a developmental window of time when auditory neurons, including neurons of the anteroventral cochlear nucleus (AVCN), depend on afferent input for survival. This period of time is often referred to as a critical period. The cellular and molecular mechanisms that underlie AVCN neuron susceptibility to deafferentation-induced death remain unknown. Here, we show that only during this critical period deafferentation of mouse AVCN neurons by in vivo cochlea removal results in rapid nuclear translocation and activation of the transcription factor NFATc4 (nuclear factor of activated T-cells isoform 4). NFAT activation is abolished by in vivo treatment with the calcineurin inhibitor FK506 and the specific NFAT-inhibitor 11R-VIVIT. Inhibition of NFAT significantly attenuates deafferentation-induced apoptosis of AVCN neurons and abolishes NFAT-mediated expression of FasL, an initiator of apoptotic pathways, in the cochlear nucleus. These data suggest that NFAT-mediated gene expression plays a role in deafferentation-induced apoptosis of cochlear nucleus neurons during a developmental critical period.
Luoma
Jessie I
JI
Graduate Program in Neuroscience, Department of Neuroscience, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
Zirpel
Lance
L
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002458:Cell Fractionation / Q000379:methods; D017626:Cochlear Nucleus / Q000166:cytology* / Q000254:growth & development; D003423:Critical Period, Psychological; D003714:Denervation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D020287:In Situ Nick-End Labeling / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology; D013997:Time Factors
D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; D050778:NFATC Transcription Factors; D009842:Oligopeptides; C121611:VIVIT peptide; D016559:Tacrolimus