title: Microcephalin coordinates mitosis in the syncytial Drosophila embryo.
abstract: Microcephalin (MCPH1) is mutated in primary microcephaly, an autosomal recessive human disorder of reduced brain size. It encodes a protein with three BRCT domains that has established roles in DNA damage signalling and the cell cycle, regulating chromosome condensation. Significant adaptive evolutionary changes in primate MCPH1 sequence suggest that changes in this gene could have contributed to the evolution of the human brain. To understand the developmental role of microcephalin we have studied its function in Drosophila. We report here that Drosophila MCPH1 is cyclically localised during the cell cycle, co-localising with DNA during interphase, but not with mitotic chromosomes. mcph1 mutant flies have a maternal effect lethal phenotype, due to mitotic arrest occurring in early syncytial cell cycles. Mitotic entry is slowed from the very first mitosis in such embryos, with prolonged prophase and metaphase stages; and frequent premature separation as well as detachment of centrosomes. As a consequence, centrosome and nuclear cycles become uncoordinated, resulting in arrested embryonic development. Phenotypic similarities with abnormal spindle (asp) and centrosomin (cnn) mutants (whose human orthologues are also mutated in primary microcephaly), suggest that further studies in the Drosophila embryo may establish a common developmental and cellular pathway underlying the human primary microcephaly phenotype.
authors: Institute of Integrative and Comparative Biology, University of Leeds, LS2 9JT, UK.
authors: Kathrin
authors: K
authors: Brunk
authors: Bertrand
authors: B
authors: Vernay
authors: Elen
authors: E
authors: Griffith
authors: Natalie L
authors: NL
authors: Reynolds
authors: David
authors: D
authors: Strutt
authors: Philip W
authors: PW
authors: Ingham
authors: Andrew P
authors: AP
authors: Jackson
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D018385:Centrosome / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000166:cytology* / Q000378:metabolism; D007399:Interphase; D008938:Mitosis; D010766:Phosphorylation
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; C526072:Mcph1 protein, Drosophila; D016203:CDC2 Protein Kinase