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First published online 25 September 2007
doi: 10.1242/jcs.016626

This Article Figures Only Full Text Full Text (PDF) Supplementary Material All Versions of this Article: jcs.016626v1 120/20/3565    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rickmyre, J. L. Articles by Lee, L. A. Search for Related Content PubMed PubMed Citation Articles by Rickmyre, J. L. Articles by Lee, L. A.

The Drosophila homolog of MCPH1, a human microcephaly gene, is required for genomic stability in the early embryo

¹ Department of Cell and Developmental Biology, Vanderbilt University Medical Center, U-4200 MRBIII, 465 21st Avenue South, Nashville, TN 37232-8240, USA
² Department of Neurobiology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA
³ Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA

^* Author for correspondence (e-mail: laura.a.lee{at}vanderbilt.edu)

Accepted 20 August 2007

Mutation of human microcephalin (MCPH1) causes autosomal recessive primary microcephaly, a developmental disorder characterized by reduced brain size. We identified mcph1, the Drosophila homolog of MCPH1, in a genetic screen for regulators of S-M cycles in the early embryo. Embryos of null mcph1 female flies undergo mitotic arrest with barrel-shaped spindles lacking centrosomes. Mutation of Chk2 suppresses these defects, indicating that they occur secondary to a previously described Chk2-mediated response to mitotic entry with unreplicated or damaged DNA. mcph1 embryos exhibit genomic instability as evidenced by frequent chromatin bridging in anaphase. In contrast to studies of human MCPH1, the ATR/Chk1-mediated DNA checkpoint is intact in Drosophila mcph1 mutants. Components of this checkpoint, however, appear to cooperate with MCPH1 to regulate embryonic cell cycles in a manner independent of Cdk1 phosphorylation. We propose a model in which MCPH1 coordinates the S-M transition in fly embryos: in the absence of mcph1, premature chromosome condensation results in mitotic entry with unreplicated DNA, genomic instability, and Chk2-mediated mitotic arrest. Finally, brains of mcph1 adult male flies have defects in mushroom body structure, suggesting an evolutionarily conserved role for MCPH1 in brain development.

Key words: Drosophila, Embryogenesis, Microcephaly, Cell cycle, Mitosis, DNA checkpoint, BRCT domain

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