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The Central Domain of MCPH1 Controls Development of the Cerebral Cortex and Gonads in Mice
Yaru Wang1, Wen Zong1, Wenli Sun1
1State Key Laboratory of Microbial Technology, Shandong University, Qingdao 250100, China.
Abstract:
MCPH1 is the first gene identified to be responsible for the human autosomal recessive disorder primary microcephaly (MCPH). Mutations in the N-terminal and central domains of MCPH1 are strongly associated with microcephaly in human patients. A recent study showed that the central domain of MCPH1, which is mainly encoded by exon 8, interacts with E3 ligase βTrCP2 and regulates the G2/M transition of the cell cycle. In order to investigate the biological functions of MCPH1's central domain, we constructed a mouse model that lacked the central domain of MCPH1 by deleting its exon 8 (designated as Mcph1-Δe8). Mcph1-Δe8 mice exhibited a reduced brain size and thinner cortex, likely caused by a compromised self-renewal capacity and premature differentiation of Mcph1-Δe8 neuroprogenitors during corticogenesis. Furthermore, Mcph1-Δe8 mice were sterile because of a loss of germ cells in the testis and ovary. The embryonic fibroblasts of Mcph1-Δe8 mice exhibited premature chromosome condensation (PCC). All of these findings indicate that Mcph1-Δe8 mice are reminiscent of MCPH1 complete knockout mice and Mcph1-ΔBR1 mice. Our study demonstrates that the central domain of MCPH1 represses microcephaly, and is essential for gonad development in mammals.
Insights
The central domain of the MCPH1 gene is crucial for normal brain development and reproductive function. Deleting this domain in mice caused microcephaly and sterility, highlighting its essential role.
Area of Science:
- Genetics
- Developmental Biology
- Neuroscience
Background:
- Primary microcephaly (MCPH) is a human autosomal recessive disorder linked to mutations in the MCPH1 gene.
- The central domain of MCPH1, encoded by exon 8, interacts with βTrCP2 and regulates cell cycle progression.
- Understanding MCPH1's central domain function is key to deciphering microcephaly pathogenesis.
Purpose of the Study:
- To investigate the biological functions of MCPH1's central domain.
- To create and analyze a mouse model lacking MCPH1's central domain (Mcph1-Δe8).
Main Methods:
- Generated a mouse model (Mcph1-Δe8) by deleting exon 8 of the Mcph1 gene.
- Phenotypically characterized Mcph1-Δe8 mice, including brain size, cortical thickness, and reproductive organs.
- Assessed embryonic fibroblasts for premature chromosome condensation (PCC).
Main Results:
- Mcph1-Δe8 mice displayed reduced brain size and thinner cortex, indicative of impaired neuroprogenitor self-renewal and premature differentiation.
- Mcph1-Δe8 mice were sterile due to germ cell loss in testes and ovaries.
- Embryonic fibroblasts from Mcph1-Δe8 mice showed premature chromosome condensation (PCC).
Conclusions:
- The central domain of MCPH1 is essential for repressing microcephaly.
- MCPH1's central domain plays a critical role in mammalian gonad development.
- The Mcph1-Δe8 mouse model effectively recapitulates phenotypes observed in other Mcph1 mutant models.
