GSBS Student Publications
GSBS Program
Neuroscience
UMMS Affiliation
Department of Neurobiology; Waddell Lab; Graduate School of Biomedical Sciences, Neuroscience Program
Date
10-15-2007
Document Type
Article
Medical Subject Headings
Animals; Cell Cycle; Cell Cycle Proteins; Chromatin; Drosophila Proteins; Drosophila melanogaster; Embryo, Nonmammalian; Genes, Insect; *Genomic Instability; Mitosis; Mushroom Bodies; Mutation; Protein Kinases; Protein-Serine-Threonine Kinases
Disciplines
Developmental Biology | Developmental Neuroscience | Genetics and Genomics | Molecular and Cellular Neuroscience
Abstract
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.
Rights and Permissions
Citation: J Cell Sci. 2007 Oct 15;120(Pt 20):3565-77. Epub 2007 Sep 25. Link to article on publisher's site
DOI of Published Version
10.1242/jcs.016626
Related Resources
Keywords
Drosophila, Embryogenesis, Microcephaly, Cell cycle, Mitosis, DNA checkpoint, BRCT domain
Journal Title
Journal of cell science
PubMed ID
17895362
Repository Citation
Rickmyre, Jamie L.; DasGupta, Shamik; Ooi, Danny Liang-Yee; Keel, Jessica; Lee, Ethan; Kirschner, Marc W.; Waddell, Scott; and Lee, Laura A., "The Drosophila homolog of MCPH1, a human microcephaly gene, is required for genomic stability in the early embryo" (2007). GSBS Student Publications. 1724.
https://escholarship.umassmed.edu/gsbs_sp/1724
Included in
Developmental Biology Commons, Developmental Neuroscience Commons, Genetics and Genomics Commons, Molecular and Cellular Neuroscience Commons
Comments
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