title: Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline.
abstract: Mutations in ASPM (abnormal spindle-like microcephaly associated) cause primary microcephaly in humans, a disorder characterized by a major reduction in brain size in the apparent absence of nonneurological anomalies. The function of the Aspm protein in neural progenitor cell expansion, as well as its localization to the mitotic spindle and midbody, suggest that it regulates brain development by a cell division-related mechanism. Furthermore, evidence that positive selection affected ASPM during primate evolution has led to suggestions that such a function changed during primate evolution. Here, we report that in Aspm mutant mice, truncated Aspm proteins similar to those causing microcephaly in humans fail to localize to the midbody during M-phase and cause mild microcephaly. A human ASPM transgene rescues this phenotype but, interestingly, does not cause a gain of function. Strikingly, truncated Aspm proteins also cause a massive loss of germ cells, resulting in a severe reduction in testis and ovary size accompanied by reduced fertility. These germline effects, too, are fully rescued by the human ASPM transgene, indicating that ASPM is functionally similar in mice and humans. Our findings broaden the spectrum of phenotypic effects of ASPM mutations and raise the possibility that positive selection of ASPM during primate evolution reflects its function in the germline.
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Pulvers
authors.forename: Jarosław
authors.initials: J
authors.lastname: Bryk
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Fish
authors.forename: Michaela
authors.initials: M
authors.lastname: Wilsch-Bräuninger
authors.forename: Yoko
authors.initials: Y
authors.lastname: Arai
authors.forename: Dora
authors.initials: D
authors.lastname: Schreier
authors.forename: Ronald
authors.initials: R
authors.lastname: Naumann
authors.forename: Jussi
authors.initials: J
authors.lastname: Helppi
authors.forename: Bianca
authors.initials: B
authors.lastname: Habermann
authors.forename: Johannes
authors.initials: J
authors.lastname: Vogt
authors.forename: Robert
authors.initials: R
authors.lastname: Nitsch
authors.forename: Attila
authors.initials: A
authors.lastname: Tóth
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Enard
authors.forename: Svante
authors.initials: S
authors.lastname: Pääbo
authors.forename: Wieland B
authors.initials: WB
authors.lastname: Huttner
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D001921:Brain / Q000002:abnormalities; D002148:Calmodulin-Binding Proteins; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000473:pathology; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007246:Infertility / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D009474:Neurons / Q000473:pathology; D009845:Oligospermia / Q000235:genetics; D010053:Ovary / Q000002:abnormalities; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D013081:Sperm Motility / Q000235:genetics; D013737:Testis / Q000002:abnormalities
chemical_list: C467202:ASPM protein, human; C512460:ASPM protein, mouse; D002148:Calmodulin-Binding Proteins; D017931:DNA Primers; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins
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