PMID- 26977770 OWN - NLM STAT- MEDLINE DCOM- 20160809 LR - 20190202 IS - 1553-7404 (Electronic) IS - 1553-7390 (Print) IS - 1553-7390 (Linking) VI - 12 IP - 3 DP - 2016 Mar TI - A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impaired BDNF Signaling in Dendritogenesis. PG - e1005907 LID - 10.1371/journal.pgen.1005907 [doi] LID - e1005907 AB - Jacob, the protein encoded by the Nsmf gene, is involved in synapto-nuclear signaling and docks an N-Methyl-D-Aspartate receptor (NMDAR)-derived signalosome to nuclear target sites like the transcription factor cAMP-response-element-binding protein (CREB). Several reports indicate that mutations in NSMF are related to Kallmann syndrome (KS), a neurodevelopmental disorder characterized by idiopathic hypogonadotropic hypogonadism (IHH) associated with anosmia or hyposmia. It has also been reported that a protein knockdown results in migration deficits of Gonadotropin-releasing hormone (GnRH) positive neurons from the olfactory bulb to the hypothalamus during early neuronal development. Here we show that mice that are constitutively deficient for the Nsmf gene do not present phenotypic characteristics related to KS. Instead, these mice exhibit hippocampal dysplasia with a reduced number of synapses and simplification of dendrites, reduced hippocampal long-term potentiation (LTP) at CA1 synapses and deficits in hippocampus-dependent learning. Brain-derived neurotrophic factor (BDNF) activation of CREB-activated gene expression plays a documented role in hippocampal CA1 synapse and dendrite formation. We found that BDNF induces the nuclear translocation of Jacob in an NMDAR-dependent manner in early development, which results in increased phosphorylation of CREB and enhanced CREB-dependent Bdnf gene transcription. Nsmf knockout (ko) mice show reduced hippocampal Bdnf mRNA and protein levels as well as reduced pCREB levels during dendritogenesis. Moreover, BDNF application can rescue the morphological deficits in hippocampal pyramidal neurons devoid of Jacob. Taken together, the data suggest that the absence of Jacob in early development interrupts a positive feedback loop between BDNF signaling, subsequent nuclear import of Jacob, activation of CREB and enhanced Bdnf gene transcription, ultimately leading to hippocampal dysplasia. FAU - Spilker, Christina AU - Spilker C AD - Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany. FAU - Nullmeier, Sven AU - Nullmeier S AD - Institute of Anatomy, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany. FAU - Grochowska, Katarzyna M AU - Grochowska KM AD - Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany. FAU - Schumacher, Anne AU - Schumacher A AD - Department of Experimental Obstetrics and Gynaecology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany. FAU - Butnaru, Ioana AU - Butnaru I AD - Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany. FAU - Macharadze, Tamar AU - Macharadze T AD - Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany. FAU - Gomes, Guilherme M AU - Gomes GM AD - Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany. FAU - Yuanxiang, PingAn AU - Yuanxiang P AD - Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany. FAU - Bayraktar, Gonca AU - Bayraktar G AD - Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany. FAU - Rodenstein, Carolin AU - Rodenstein C AD - Institute of Anatomy, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany. FAU - Geiseler, Carolin AU - Geiseler C AD - Institute of Anatomy, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany. FAU - Kolodziej, Angela AU - Kolodziej A AD - Department of Systems Physiology of Learning, Leibniz Institute for Neurobiology, Magdeburg, Germany. FAU - Lopez-Rojas, Jeffrey AU - Lopez-Rojas J AD - Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany. FAU - Montag, Dirk AU - Montag D AD - Special Laboratory Neurogenetics, Leibniz Institute for Neurobiology, Magdeburg, Germany. FAU - Angenstein, Frank AU - Angenstein F AD - Functional Neuroimaging Group, Deutsches Zentrum fur Neurodegenerative Erkrankungen (DZNE), and Special Laboratory for Noninvasive Brain Imaging, Leibniz Institute for Neurobiology, Magdeburg, Germany. FAU - Bar, Julia AU - Bar J AD - Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany. AD - University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Emmy-Noether Group 'Neuronal Protein Transport', Hamburg, Germany. FAU - D'Hanis, Wolfgang AU - D'Hanis W AD - Institute of Anatomy, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany. FAU - Roskoden, Thomas AU - Roskoden T AD - Institute of Anatomy, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany. FAU - Mikhaylova, Marina AU - Mikhaylova M AD - Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany. AD - University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Emmy-Noether Group 'Neuronal Protein Transport', Hamburg, Germany. FAU - Budinger, Eike AU - Budinger E AD - Department of Systems Physiology of Learning, Leibniz Institute for Neurobiology, Magdeburg, Germany. FAU - Ohl, Frank W AU - Ohl FW AD - Department of Systems Physiology of Learning, Leibniz Institute for Neurobiology, Magdeburg, Germany. FAU - Stork, Oliver AU - Stork O AD - Institute of Biology, Otto von Guericke University, Magdeburg, Germany. FAU - Zenclussen, Ana C AU - Zenclussen AC AD - Department of Experimental Obstetrics and Gynaecology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany. FAU - Karpova, Anna AU - Karpova A AD - Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany. FAU - Schwegler, Herbert AU - Schwegler H AD - Institute of Anatomy, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany. FAU - Kreutz, Michael R AU - Kreutz MR AD - Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany. AD - University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Leibniz Group 'Dendritic Organelles and Synaptic Function', Hamburg, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160315 PL - United States TA - PLoS Genet JT - PLoS genetics JID - 101239074 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Jacob protein, mouse) RN - 0 (Nerve Tissue Proteins) RN - 0 (RNA, Messenger) RN - 33515-09-2 (Gonadotropin-Releasing Hormone) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/*genetics/metabolism MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - Dendrites/*metabolism MH - Gene Expression Regulation, Developmental MH - Gonadotropin-Releasing Hormone/metabolism MH - Hippocampus/*growth & development/metabolism MH - Mice MH - Mice, Knockout MH - Nerve Tissue Proteins/*genetics MH - Neurons/metabolism MH - Phosphorylation MH - RNA, Messenger/biosynthesis MH - Signal Transduction MH - Synapses/genetics/metabolism PMC - PMC4792503 COIS- The authors have declared that no competing interests exist. EDAT- 2016/03/16 06:00 MHDA- 2016/08/10 06:00 PMCR- 2016/03/15 CRDT- 2016/03/16 06:00 PHST- 2015/10/18 00:00 [received] PHST- 2016/02/08 00:00 [accepted] PHST- 2016/03/16 06:00 [entrez] PHST- 2016/03/16 06:00 [pubmed] PHST- 2016/08/10 06:00 [medline] PHST- 2016/03/15 00:00 [pmc-release] AID - PGENETICS-D-15-02541 [pii] AID - 10.1371/journal.pgen.1005907 [doi] PST - epublish SO - PLoS Genet. 2016 Mar 15;12(3):e1005907. doi: 10.1371/journal.pgen.1005907. eCollection 2016 Mar.