| First Author | Liu X | Year | 2021 |
| Journal | Cell Death Dis | Volume | 12 |
| Issue | 2 | Pages | 143 |
| PubMed ID | 33542216 | Mgi Jnum | J:307535 |
| Mgi Id | MGI:6721174 | Doi | 10.1038/s41419-021-03406-3 |
| Citation | Liu X, et al. (2021) The N-terminal BRCT domain determines MCPH1 function in brain development and fertility. Cell Death Dis 12(2):143 |
| abstractText | MCPH1 is a causal gene for the neurodevelopmental disorder, human primary microcephaly (MCPH1, OMIM251200). Most pathogenic mutations are located in the N-terminal region of the gene, which encodes a BRCT domain, suggesting an important function of this domain in brain size determination. To investigate the specific function of the N-terminal BRCT domain in vivo, we generated a mouse model lacking the N'-BRCT domain of MCPH1 (referred as Mcph1-DeltaBR1). These mutant mice are viable, but exhibit reduced brain size, with a thinner cortex due to a reduction of neuroprogenitor populations and premature neurogenic differentiation. Mcph1-DeltaBR1 mice (both male and female) are infertile; however, almost all female mutants develop ovary tumours. Mcph1-DeltaBR1 MEF cells exhibit a defect in DNA damage response and DNA repair, and show the premature chromosome condensation (PCC) phenotype, a hallmark of MCPH1 patient cells and also Mcph1 knockout cells. In comparison with Mcph1 complete knockout mice, Mcph1-DeltaBR1 mice faithfully reproduce all phenotypes, indicating an essential role of the N-terminal BRCT domain for the physiological function of MCPH1 in the control of brain size and gonad development as well as in multiple cellular processes. |
