Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline

Jeremy N. Pulvers, Jarosław Bryk, Jennifer L. Fish, Michaela Wilsch-Bräuninger, Yoko Arai, Dora Schreier, Ronald Naumann, Jussi Helppi, Bianca Habermann, Johannes Vogt, Robert Nitsch, Attila Tóth, Wolfgang Enard, Svante Pääbo, Wieland B. Huttner

Research output: Contribution to journalArticle

98 Citations (Scopus)

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.

LanguageEnglish
Pages16595-16600
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number38
DOIs
Publication statusPublished - 21 Sep 2010
Externally publishedYes

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Microcephaly
Mutation
Primates
Transgenes
Cell Division
Spindle Apparatus
Brain
Germ Cells
Fertility
Testis
Ovary

Cite this

Pulvers, Jeremy N. ; Bryk, Jarosław ; Fish, Jennifer L. ; Wilsch-Bräuninger, Michaela ; Arai, Yoko ; Schreier, Dora ; Naumann, Ronald ; Helppi, Jussi ; Habermann, Bianca ; Vogt, Johannes ; Nitsch, Robert ; Tóth, Attila ; Enard, Wolfgang ; Pääbo, Svante ; Huttner, Wieland B. / Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 38. pp. 16595-16600.
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Pulvers, JN, Bryk, J, Fish, JL, Wilsch-Bräuninger, M, Arai, Y, Schreier, D, Naumann, R, Helppi, J, Habermann, B, Vogt, J, Nitsch, R, Tóth, A, Enard, W, Pääbo, S & Huttner, WB 2010, 'Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 38, pp. 16595-16600. https://doi.org/10.1073/pnas.1010494107

Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline. / Pulvers, Jeremy N.; Bryk, Jarosław; Fish, Jennifer L.; Wilsch-Bräuninger, Michaela; Arai, Yoko; Schreier, Dora; Naumann, Ronald; Helppi, Jussi; Habermann, Bianca; Vogt, Johannes; Nitsch, Robert; Tóth, Attila; Enard, Wolfgang; Pääbo, Svante; Huttner, Wieland B.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 38, 21.09.2010, p. 16595-16600.

Research output: Contribution to journalArticle

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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.

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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.

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