title: Mir-592 regulates the induction and cell death-promoting activity of p75NTR in neuronal ischemic injury.
abstract: The neurotrophin receptor p75(NTR) has been implicated in mediating neuronal apoptosis after injury to the CNS. Despite its frequent induction in pathologic states, there is limited understanding of the mechanisms that regulate p75(NTR) expression after injury. Here, we show that after focal cerebral ischemia in vivo or oxygen-glucose deprivation in organotypic hippocampal slices or neurons, p75(NTR) is rapidly induced. A concomitant induction of proNGF, a ligand for p75(NTR), is also observed. Induction of this ligand/receptor system is pathologically relevant, as a decrease in apoptosis, after oxygen-glucose deprivation, is observed in hippocampal neurons or slices after delivery of function-blocking antibodies to p75(NTR) or proNGF and in p75(NTR) and ngf haploinsufficient slices. Furthermore, a significant decrease in infarct volume was noted in p75(NTR)-/- mice compared with the wild type. We also investigated the regulatory mechanisms that lead to post-ischemic induction of p75(NTR). We demonstrate that induction of p75(NTR) after ischemic injury is independent of transcription but requires active translation. Basal levels of p75(NTR) in neurons are maintained in part by the expression of microRNA miR-592, and an inverse correlation is seen between miR-592 and p75(NTR) levels in the adult brain. After cerebral ischemia, miR-592 levels fall, with a corresponding increase in p75(NTR) levels. Importantly, overexpression of miR-592 in neurons decreases the level of ischemic injury-induced p75(NTR) and attenuates activation of pro-apoptotic signaling and cell death. These results identify miR-592 as a key regulator of p75(NTR) expression and point to a potential therapeutic candidate to limit neuronal apoptosis after ischemic injury.
authors.affiliation: Department of Medicine and Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10065, and Interdisciplinary Center for Neurosciences, Department of Neuroanatomy, University of Heidelberg, INF 307, D69120 Heidelberg, Germany.
authors.forename: Krithi
authors.initials: K
authors.lastname: Irmady
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Jackman
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Padow
authors.forename: Neelam
authors.initials: N
authors.lastname: Shahani
authors.forename: Laura Andres
authors.initials: LA
authors.lastname: Martin
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.forename: Klaus
authors.initials: K
authors.lastname: Unsicker
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Hempstead
mesh_terms: D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D000860:Hypoxia; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D011498:Protein Precursors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: C587924:MIRN592 microRNA, mouse; D035683:MicroRNAs; D011498:Protein Precursors; D034741:RNA, Small Interfering; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; C489226:pro-nerve growth factor, mouse; D020932:Nerve Growth Factor; D005947:Glucose
keywords: NGF; ischemia; microRNA; neurotrophin; p75NTR; stroke