title: Establishment of a mouse model with misregulated chromosome condensation due to defective Mcph1 function.
abstract: Mutations in the human gene MCPH1 cause primary microcephaly associated with a unique cellular phenotype with premature chromosome condensation (PCC) in early G2 phase and delayed decondensation post-mitosis (PCC syndrome). The gene encodes the BRCT-domain containing protein microcephalin/BRIT1. Apart from its role in the regulation of chromosome condensation, the protein is involved in the cellular response to DNA damage. We report here on the first mouse model of impaired Mcph1-function. The model was established based on an embryonic stem cell line from BayGenomics (RR0608) containing a gene trap in intron 12 of the Mcph1 gene deleting the C-terminal BRCT-domain of the protein. Although residual wild type allele can be detected by quantitative real-time PCR cell cultures generated from mouse tissues bearing the homozygous gene trap mutation display the cellular phenotype of misregulated chromosome condensation that is characteristic for the human disorder, confirming defective Mcph1 function due to the gene trap mutation. While surprisingly the DNA damage response (formation of repair foci, chromosomal breakage, and G2/M checkpoint function after irradiation) appears to be largely normal in cell cultures derived from Mcph1(gt/gt) mice, the overall survival rates of the Mcph1(gt/gt) animals are significantly reduced compared to wild type and heterozygous mice. However, we could not detect clear signs of premature malignant disease development due to the perturbed Mcph1 function. Moreover, the animals show no obvious physical phenotype and no reduced fertility. Body and brain size are within the range of wild type controls. Gene expression on RNA and protein level did not reveal any specific pattern of differentially regulated genes. To the best of our knowledge this represents the first mammalian transgenic model displaying a defect in mitotic chromosome condensation and is also the first mouse model for impaired Mcph1-function.
authors.affiliation: Institute for Medical Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Trimborn
authors.forename: Mahdi
authors.initials: M
authors.lastname: Ghani
authors.forename: Diego J
authors.initials: DJ
authors.lastname: Walther
authors.forename: Monika
authors.initials: M
authors.lastname: Dopatka
authors.forename: Véronique
authors.initials: V
authors.lastname: Dutrannoy
authors.forename: Andreas
authors.initials: A
authors.lastname: Busche
authors.forename: Franziska
authors.initials: F
authors.lastname: Meyer
authors.forename: Stefanie
authors.initials: S
authors.lastname: Nowak
authors.forename: Jean
authors.initials: J
authors.lastname: Nowak
authors.forename: Claus
authors.initials: C
authors.lastname: Zabel
authors.forename: Joachim
authors.initials: J
authors.lastname: Klose
authors.forename: Veronica
authors.initials: V
authors.lastname: Esquitino
authors.forename: Masoud
authors.initials: M
authors.lastname: Garshasbi
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Kuss
authors.forename: Hans-Hilger
authors.initials: HH
authors.lastname: Ropers
authors.forename: Susanne
authors.initials: S
authors.lastname: Mueller
authors.forename: Charlotte
authors.initials: C
authors.lastname: Poehlmann
authors.forename: Ioannis
authors.initials: I
authors.lastname: Gavvovidis
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
authors.forename: Karl
authors.initials: K
authors.lastname: Sperling
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Neitzel
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019457:Chromosome Breakage; D033481:Chromosomes, Mammalian / Q000235:genetics*; D003598:Cytoskeletal Proteins; D004249:DNA Damage; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D023421:Models, Animal; D020411:Oligonucleotide Array Sequence Analysis; D040901:Proteomics; D016019:Survival Analysis
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D003598:Cytoskeletal Proteins; C547654:MCPH1 protein, mouse