TY - JOUR
T1 - Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline
AU - Pulvers, Jeremy N.
AU - Bryk, Jarosław
AU - Fish, Jennifer L.
AU - Wilsch-Bräuninger, Michaela
AU - Arai, Yoko
AU - Schreier, Dora
AU - Naumann, Ronald
AU - Helppi, Jussi
AU - Habermann, Bianca
AU - Vogt, Johannes
AU - Nitsch, Robert
AU - Tóth, Attila
AU - Enard, Wolfgang
AU - Pääbo, Svante
AU - Huttner, Wieland B.
PY - 2010/9/21
Y1 - 2010/9/21
N2 - 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.
AB - 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.
KW - Cerebral cortex
KW - Evolution
KW - Fertility
KW - Germ cells
KW - Neural stem cells
UR - http://www.scopus.com/inward/record.url?scp=78049310300&partnerID=8YFLogxK
UR - http://www.pnas.org/site/aboutpnas/index.xhtml
U2 - 10.1073/pnas.1010494107
DO - 10.1073/pnas.1010494107
M3 - Article
C2 - 20823249
AN - SCOPUS:78049310300
VL - 107
SP - 16595
EP - 16600
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 38
ER -