title: Sun1 deficiency leads to cerebellar ataxia in mice.
abstract: Migration and organization of the nucleus are essential for the proliferation and differentiation of cells, including neurons. However, the relationship between the positioning of the nucleus and cellular morphogenesis remains poorly understood. Inherited recessive cerebellar ataxia has been attributed to mutations in SYNE1, a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex. Regardless, Syne1-mutant mice present with normal cerebellar development. The Sad1-Unc-84 homology (SUN)-domain proteins are located at the inner nuclear membrane and recruit Syne proteins through the KASH domain to the outer nuclear membrane. Here, we report an unrecognized contribution of Sun1 and Sun2 to the postnatal development of murine cerebellum. Mice depleted of Sun1 showed a marked reduction in the cerebellar volume, and this phenotype is exacerbated with additional loss of a Sun2 allele. Consistent with these histological changes, Sun1(-/-) and Sun1(-/-)Sun2(+/-) mice exhibited defective motor coordination. Results of immunohistochemical analyses suggested that Sun1 is highly expressed in Purkinje cells and recruits Syne2 to the periphery of the nucleus. Approximately 33% of Purkinje cells in Sun1(-/-) mice and 66% of Purkinje cells in Sun1(-/-)Sun2(+/-) mice were absent from the surface of the internal granule layer (IGL), whereas the proliferation and migration of granule neurons were unaffected. Furthermore, the Sun1(-/-)Sun2(+/-) Purkinje cells exhibited retarded primary dendrite specification, reduced dendritic complexity and aberrant patterning of synapses. Our findings reveal a cell-type-specific role for Sun1 and Sun2 in nucleokinesis during cerebellar development, and we propose the use of Sun-deficient mice as a model for studying cerebellar ataxia that is associated with mutation of human SYNE genes or loss of Purkinje cells.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan.
authors.forename: Jing-Ya
authors.initials: JY
authors.lastname: Wang
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Hospital, Taipei 10048, Taiwan Center of Genomic Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10048, Taiwan.
authors.forename: I-Shing
authors.initials: IS
authors.lastname: Yu
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan.
authors.forename: Chien-Chi
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Chia-Yen
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan.
authors.forename: Wan-Ping
authors.initials: WP
authors.lastname: Wang
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Hospital, Taipei 10048, Taiwan Center of Genomic Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10048, Taiwan Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 10048, Taiwan.
authors.forename: Shu-Wha
authors.initials: SW
authors.lastname: Lin
authors.affiliation: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kuan-Teh
authors.initials: KT
authors.lastname: Jeang
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan ychi@nhri.org.tw.
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Chi
mesh_terms: D000818:Animals; D002524:Cerebellar Ataxia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002531:Cerebellum / Q000196:embryology / Q000473:pathology; D003712:Dendrites / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency* / Q000378:metabolism; D009043:Motor Activity; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009685:Nuclear Envelope / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D021381:Protein Transport; D011689:Purkinje Cells / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D034501:Telomere-Binding Proteins / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C464932:SUN1 protein, mouse; C520338:Sun2 protein, mouse; C485903:Syne2 protein, mouse; D034501:Telomere-Binding Proteins
keywords: Cerebellar ataxia; LINC complex; Sun1