title: A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impaired BDNF Signaling in Dendritogenesis.
abstract: 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.
authors.affiliation: Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Spilker
authors.affiliation: Institute of Anatomy, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Nullmeier
authors.affiliation: Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Grochowska
authors.affiliation: Department of Experimental Obstetrics and Gynaecology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Schumacher
authors.affiliation: Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Ioana
authors.initials: I
authors.lastname: Butnaru
authors.affiliation: Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Tamar
authors.initials: T
authors.lastname: Macharadze
authors.affiliation: Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Guilherme M
authors.initials: GM
authors.lastname: Gomes
authors.affiliation: Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: PingAn
authors.initials: P
authors.lastname: Yuanxiang
authors.affiliation: Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Gonca
authors.initials: G
authors.lastname: Bayraktar
authors.affiliation: Institute of Anatomy, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Rodenstein
authors.affiliation: Institute of Anatomy, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Geiseler
authors.affiliation: Department of Systems Physiology of Learning, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Kolodziej
authors.affiliation: Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lopez-Rojas
authors.affiliation: Special Laboratory Neurogenetics, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Montag
authors.affiliation: Functional Neuroimaging Group, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), and Special Laboratory for Noninvasive Brain Imaging, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Angenstein
authors.affiliation: Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.|University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Emmy-Noether Group 'Neuronal Protein Transport', Hamburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Bär
authors.affiliation: Institute of Anatomy, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: D'Hanis
authors.affiliation: Institute of Anatomy, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Roskoden
authors.affiliation: Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.|University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Emmy-Noether Group 'Neuronal Protein Transport', Hamburg, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Mikhaylova
authors.affiliation: Department of Systems Physiology of Learning, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Eike
authors.initials: E
authors.lastname: Budinger
authors.affiliation: Department of Systems Physiology of Learning, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Frank W
authors.initials: FW
authors.lastname: Ohl
authors.affiliation: Institute of Biology, Otto von Guericke University, Magdeburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Stork
authors.affiliation: Department of Experimental Obstetrics and Gynaecology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Zenclussen
authors.affiliation: Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Karpova
authors.affiliation: Institute of Anatomy, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Schwegler
authors.affiliation: Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.|University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology, ZMNH, Leibniz Group 'Dendritic Organelles and Synaptic Function', Hamburg, Germany.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Kreutz
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D006624:Hippocampus / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction; D013569:Synapses / Q000235:genetics / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; C544462:Jacob protein, mouse; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D007987:Gonadotropin-Releasing Hormone