title: Kif18a is specifically required for mitotic progression during germ line development.
abstract: Genome integrity in the developing germ line is strictly required for fecundity. In proliferating somatic cells and in germ cells, there are mitotic checkpoint mechanisms that ensure accurate chromosome segregation and euploidy. There is growing evidence of mitotic cell cycle components that are uniquely required in the germ line to ensure genome integrity. We previously showed that the primary phenotype of germ cell deficient 2 (gcd2) mutant mice is infertility due to germ cell depletion during embryogenesis. Here we show that the underlying mutation is a mis-sense mutation, R308K, in the motor domain of the kinesin-8 family member, KIF18A, a protein that is expressed in a variety of proliferative tissues and is a key regulator of chromosome alignment during mitosis. Despite the conservative nature of the mutation, we show that its functional consequences are equivalent to KIF18A deficiency in HeLa cells. We also show that somatic cells progress through mitosis, despite having chromosome alignment defects, while germ cells with similar chromosome alignment defects undergo mitotic arrest and apoptosis. Our data provide evidence for differential requirements for chromosome alignment in germ and somatic cells and show that Kif18a is one of a growing number of genes that are specifically required for cell cycle progression in proliferating germ cells.
authors.affiliation: The Jackson Laboratory, Genetic Resource Science, Bar Harbor, ME 04609.
authors.forename: Anne
authors.initials: A
authors.lastname: Czechanski
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405.
authors.forename: Haein
authors.initials: H
authors.lastname: Kim
authors.affiliation: The Jackson Laboratory, Genetic Resource Science, Bar Harbor, ME 04609.
authors.forename: Candice
authors.initials: C
authors.lastname: Byers
authors.affiliation: The Jackson Laboratory, Genetic Resource Science, Bar Harbor, ME 04609.
authors.forename: Ian
authors.initials: I
authors.lastname: Greenstein
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405.
authors.forename: Jason
authors.initials: J
authors.lastname: Stumpff
authors.affiliation: The Jackson Laboratory, Genetic Resource Science, Bar Harbor, ME 04609.
authors.forename: Laura G
authors.initials: LG
authors.lastname: Reinholdt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D003001:Cloning, Molecular; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing; D005822:Genetic Vectors / Q000235:genetics; D005854:Germ Cells / Q000502:physiology*; D006367:HeLa Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D016547:Kinesins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008938:Mitosis / Q000235:genetics / Q000502:physiology*; D020125:Mutation, Missense / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018797:Cell Cycle Proteins; C000600109:KIF18a protein, mouse; D034741:RNA, Small Interfering; D016547:Kinesins
keywords: Cell cycle; Gametogenesis; Germ cells; Kinesin; Laboratory mouse; Mitosis; Mitotic spindle
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