The Central Domain of MCPH1 Controls Development of the Cerebral Cortex and Gonads in Mice

Cells. 2022 Aug 31;11(17):2715. doi: 10.3390/cells11172715.

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.

Keywords: MCPH1; brain development; central domain; gonad development; microcephaly.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins* / genetics
  • Cell Cycle Proteins* / metabolism
  • Cerebral Cortex / metabolism
  • Cytoskeletal Proteins* / genetics
  • Cytoskeletal Proteins* / metabolism
  • Female
  • Gonads / metabolism
  • Male
  • Mammals / metabolism
  • Mice
  • Mice, Knockout
  • Microcephaly* / genetics
  • Microcephaly* / metabolism

Substances

  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • MCPH1 protein, mouse

Supplementary concepts

  • Autosomal Recessive Primary Microcephaly
  • Microcephaly, Primary Autosomal Recessive, 1

Grants and funding

This research was supported by the DFG grant to Z.-Q.W. (WA2627/2-2). T.L is supported by Grant Nos. KF2020005 and KF2021008 from NHC Key Laboratory of Birth Defect for Research and Prevention (Hunan Provincial Maternal and Child Health Care Hospital, Changsha, China), Grant No. 31770871 from the National Natural Science Foundation of China, and Qilu Youth Scholar Startup Funding of Shandong University.