title: Calcium-induced apoptosis of developing cerebellar granule neurons depends causally on NGFI-B.
abstract: Immediate early gene nerve growth factor-induced clone B (NGFI-B), a nuclear receptor important for differentiation and apoptosis, is expressed in mice and rat cerebellum from an early stage of postnatal development. Following apoptotic stimuli NGFI-B translocates to mitochondria to initiate cell death processes. Controlled cell death is critical for correct cerebellar development. Immunohistochemical analysis of NGFI-B in sections of mice cerebella showed NGFI-B to be expressed in granule neurons in vivo at a time (P8-11) when apoptosis is known to occur. The importance of NGFI-B for apoptosis of cultured rat cerebellar granule neurons was investigated by inducing apoptosis with calcium ionophore A23187 (CaI, 0.1μM). Imaging studies of gfp-tagged NGFI-B confirmed that mitochondrial translocation of NGFI-B occurred following treatment with CaI and was reduced by addition of 9-cis-retinoic acid (1μM), a retinoid X receptor (RXR) agonist that prevents dimerization of RXR and NGFI-B that is known to occur before translocation. Consequently, 9-cis-retinoic acid partly reduced cell death. To address the causality of NGFI-B in apoptosis further, knock-down by siRNA was performed and it removed 85% of the NGFI-B protein. This resulted in a complete inhibition of apoptosis after CaI exposure. Together these findings suggest that NGFI-B plays a role in controlling correct cerebellar development.
authors: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway.
authors: Lars Peter Engeset
authors: LP
authors: Austdal
authors: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway.
authors: Gro H
authors: GH
authors: Mathisen
authors: Department of Pathology, Oslo University Hospital, Ullevål, Norway.
authors: Else Marit
authors: EM
authors: Løberg
authors: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway. Electronic address: r.e.paulsen@farmasi.uio.no.
authors: Ragnhild E
authors: RE
authors: Paulsen
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology*; D061207:Calcium Ionophores / Q000494:pharmacology; D002465:Cell Movement / Q000502:physiology; D002531:Cerebellum / Q000166:cytology* / Q000254:growth & development*; D003561:Cytarabine / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000187:drug effects*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D047488:Retinoid X Receptors / Q000378:metabolism; D018709:Statistics, Nonparametric; D013997:Time Factors; D014162:Transfection
chemical_list: D061207:Calcium Ionophores; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D034741:RNA, Small Interfering; D047488:Retinoid X Receptors; D003561:Cytarabine; D000001:Calcimycin; D002118:Calcium
keywords: Apoptosis; Calcium; Cerebellar granule neurons; Development; NGFI-B; Translocation