title: Bcl-2 increases stroke-induced striatal neurogenesis in adult brains by inhibiting BMP-4 function via activation of β-catenin signaling.
abstract: Our previous experiments suggest that treatment with Bcl-2 increases proliferation and differentiation of neuronal progenitors induced by ischemic injury and ameliorates neurological functional deficits after stroke. However, in addition to its traditional anti-apoptotic effect, little is known about the concrete molecular modulation mechanism. In this study, Bcl-2-expressing plasmids were injected into the lateral ventricle of rat brains immediately following a 30-min occlusion of the middle cerebral artery to determine the role of Bcl-2 in adult neurogenesis. Bcl-2 overexpression reduced ischemic infarct and astrogenesis, and enhanced ischemia-induced striatal neurogenesis. We further found that Bcl-2 increased β-catenin, a key mediator of canonical Wnt/β-catenin signaling pathway, and reduced bone morphogenetic proteins-4 (BMP-4) expression in the ipsilateral striatum following ischemia. Treatment of stroke with β-catenin siRNA (i.c.v.) showed that β-catenin siRNA antagonized Bcl-2 neuroprotection against ischemic brain injury. More interestingly, β-catenin siRNA simultaneously abolished Bcl-2-mediated reduction of BMP-4 expression and enhancement of neurogenesis in the ipsilateral striatum. This effect is independent of Noggin, the known BMP antagonist. These findings highlight a new regulatory mechanism that Bcl-2 elevates ischemia-induced striatal neurogenesis by down-regulating expression of BMP-4 via activation of the Wnt/β-catenin signaling pathway in adult rat brains.
authors.affiliation: Department of Neurobiology and Institute for Biomedical Science, State Key Laboratory of Medical Neurobiology, Shanghai Medical College of Fudan University, Shanghai 200032, PR China.
authors.forename: Zhi-Nian
authors.initials: ZN
authors.lastname: Lei
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Lin-Mei
authors.initials: LM
authors.lastname: Zhang
authors.forename: Ya-Lin
authors.initials: YL
authors.lastname: Huang
authors.forename: Feng-Yan
authors.initials: FY
authors.lastname: Sun
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000037:antagonists & inhibitors* / Q000502:physiology; D003342:Corpus Striatum / Q000473:pathology*; D007150:Immunohistochemistry; D008297:Male; D018613:Microscopy, Confocal; D055495:Neurogenesis / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D020521:Stroke / Q000473:pathology* / Q000503:physiopathology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C525811:Bmp4 protein, rat; D055415:Bone Morphogenetic Protein 4; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D051176:beta Catenin