MCPH1-mediated Network Regulates Neurogenesis and Neural Stem Cell Fate

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Human primary microcephaly (MCPH) is an autosomal recessive neurodevelopmental disorder, which is characterized by a marked reduction in brain size with a normal architecture and non-progressive mental retardation. MCPH genes may present a consequence of an important positive selection for the enlargement of the human brain size during evolution. The MCPH1 gene that encodes Microcephalin or MCPH1 has been shown to be involved in cell cycle checkpoint and DNA damage response (DDR). During the last period of DFG support we showed that an MCPH1 deletion in mice affects the Chk1-Cdk1 activation leading to a premature mitotic entry, which distracts cell division mode and exhausts the neuroprogenitor pool. We also found that the MCPH1 deletion sensitizes neuroprogenitors to DDR induced apoptosis. Recently, we discovered that MCPH1 interacts with the ubiquitin E3 ligase betaTrCP2 and promotes its activity to degrade Cdc25A, thereby regulating the mitotic entry. Furthermore, MCPH1 is ubiquitylated and degraded during the mitosis transition by another E3 ligase APC/CCdh, indicating an importance of the MCPH1 turnover during mitosis. A dynamic homeostasis of MCPH1 in association with betaTrCP2 and APC/CCdh1 ensures the mitotic entry and exit and a proper neurogenesis. Thus, the interaction partners of MCPH1 are thought to be important coordinators to control the fate and pools of neuroprogenitors. To decipher how MCPH1 coordinates cellular activities to control the fate and pools of neuroprogenitors remains elusive. In this project we propose:(1) To dissect the functional domains of MCPH1 and its interaction partners in brain size determination and neurodegeneration. (2) To study the MCPH1-betaTrCP2-Cdc25A mediated pathway in regulating the mitotic entry and neurogenesis.(3) To identify novel molecular pathways of MCPH1 which drive the MCPH1 function in neurogenesis and neural stem cell fate determination. We will take the following approaches: (i) The characterization of mice carrying the domain specific mutant MCPH1; (ii) The construction of MCPH1 mutant mice in which the specific betaTrCP2 interaction domain is deleted; (iii) The proteomic screening and functional test of novel MCPH1 partners in the mitotic entry and neural stem cell fate determination. Our study will contribute to the understanding of brain size control. This project is very important for understanding the mechanisms that may be generally underlying microcephaly and cognitive disorders. Such knowledge may facilitate the development of novel strategies for the treatment of neurodegenerative components.