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Waltereit, R.* ; Leimer, U.* ; von Bohlen und Halbach, O.* ; Panke, J.* ; Hölter, S.M. ; Garrett, L. ; Wittig, K.* ; Schneider, M.* ; Schmitt, C.* ; Calzada-Wack, J. ; Neff, F. ; Becker, L. ; Prehn, C. ; Kutscherjawy, S.* ; Endris, V.* ; Bacon, C.* ; Fuchs, H. ; Gailus-Durner, V. ; Berger, S.* ; Schönig, K.* ; Adamski, J. ; Klopstock, T.* ; Esposito, I. ; Wurst, W. ; Hrabě de Angelis, M. ; Rappold, G.* ; Wieland, T.* ; Bartsch, D.*

Srgap3-/- mice present a neurodevelopmental disorder with schizophrenia-related intermediate phenotypes.

FASEB J. 26, 4418-4428 (2012)
DOI PMC
Mutations in the SRGAP3 gene residing on chromosome 3p25 have previously been associated with intellectual disability. Genome-wide association studies have also revealed SRGAP3, together with genes from the same cellular network, as risk genes for schizophrenia. SRGAP3 regulates cytoskeletal dynamics through the RHO protein RAC1. RHO proteins are known to be involved in cytoskeletal reorganization during brain development to control processes such as synaptic plasticity. To elucidate the importance of SRGAP3 in brain development, we generated Srgap3-knockout mice. Ten percent of these mice developed a hydrocephalus and died before adulthood. Surviving mice showed various neuroanatomical changes, including enlarged lateral ventricles, white matter tracts, and dendritic spines together with molecular changes, including an increased basal activity of RAC1. Srgap3(-/-) mice additionally exhibited a complex behavioral phenotype. Behavioral studies revealed an impaired spontaneous alternation and social behavior, while long-term memory was unchanged. The animals also had tics. Lower locomotor activity was observed in male Srgap3(-/-) only. Srgap3(-/-) mice showed increased methylphenidate stimulation in males and an impaired prepulse inhibition in females. Together, the results show neurodevelopmental aberration in Srgap3(-/-) mice, with many of the observed phenotypes matching several schizophrenia-related intermediate phenotypes. Mutations of SRGAP3 may thus contribute to various neurodevelopmental disorders.
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Publication type Article: Journal article
Document type Scientific Article
Keywords intellectual disability; hydrocephalus; knockout mouse; RHO proteins; polygenetic disease
Language english
Publication Year 2012
HGF-reported in Year 2012
ISSN (print) / ISBN 0892-6638
e-ISSN 1530-6860
Journal FASEB Journal
Quellenangaben Volume: 26, Issue: 11, Pages: 4418-4428 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Bethesda, Md.
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)
Institute of Pathology (PATH)
Institute of Experimental Genetics (IEG)
Molekulare Endokrinologie und Metabolismus (MEM)
POF-Topic(s) 30204 - Cell Programming and Repair
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30201 - Metabolic Health
Research field(s) Genetics and Epidemiology
Enabling and Novel Technologies
PSP Element(s) G-500500-001
G-500300-001
G-500600-003
G-500600-001
G-505600-001
PubMed ID 22820399
DOI 10.1096/fj.11-202317
Scopus ID 84868275867
Erfassungsdatum 2012-08-03
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