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Published on: May 22, 2019
Establishment of a mouse model with misregulated chromosome condensation due to defective Mcph1 function
Marc Trimborn1, Mahdi Ghani, Diego J Walther
1Institute for Medical Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
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.
Insights
Researchers developed a mouse model for MCPH1 gene mutations, revealing defects in chromosome condensation. Despite normal DNA damage response, these mice show reduced survival, offering insights into primary microcephaly.
Area of Science:
- Genetics and Molecular Biology
- Cell Biology
- Developmental Biology
Background:
- Mutations in the human MCPH1 gene cause primary microcephaly, characterized by premature chromosome condensation (PCC) syndrome.
- MCPH1 encodes microcephalin/BRIT1, a protein crucial for chromosome condensation and DNA damage response.
- A functional mouse model is needed to study MCPH1's role in vivo.
Purpose of the Study:
- To create and characterize the first mouse model of impaired Mcph1 function.
- To investigate the cellular and physiological consequences of Mcph1 deficiency in mammals.
- To validate the gene trap mutation's effect on chromosome condensation and DNA damage response.
Main Methods:
- Generation of a mouse model using a gene trap in the Mcph1 gene (RR0608) targeting the C-terminal BRCT-domain.
- Analysis of cell cultures from homozygous gene trap mutant mice (Mcph1(gt/gt)) for chromosome condensation phenotypes.
- Assessment of DNA damage response (repair foci, chromosomal breakage, G2/M checkpoint) and animal survival rates.
Main Results:
- Mcph1(gt/gt) cell cultures exhibit misregulated chromosome condensation, characteristic of PCC syndrome.
- DNA damage response pathways appear largely normal in mutant cell cultures.
- Mcph1(gt/gt) mice show significantly reduced overall survival rates but no obvious physical defects, reduced fertility, or altered brain size.
Conclusions:
- The generated mouse model successfully replicates the cellular phenotype of defective Mcph1 function.
- Impaired Mcph1 function leads to reduced animal survival, independent of overt DNA damage response defects.
- This study presents the first mammalian model for defective mitotic chromosome condensation and impaired Mcph1 function.
