Abstract
MCPH1, or BRIT1, is often mutated in human primary microcephaly type 1, a neurodevelopmental disorder characterized by a smaller brain size at birth, due to its dysfunction in regulating the proliferation and self-renewal of neuroprogenitor cells. In the last 20 years or so, genetic and cellular studies have identified MCPH1 as a multifaceted protein in various cellular functions, including DNA damage signaling and repair, the regulation of chromosome condensation, cell-cycle progression, centrosome activity and the metabolism. Yet, genetic and animal model studies have revealed an unpredicted essential function of MPCH1 in gonad development and tumorigenesis, although the underlying mechanism remains elusive. These studies have begun to shed light on the role of MPCH1 in controlling various pathobiological processes of the disorder. Here, we summarize the biological functions of MCPH1, and lessons learnt from cellular and mouse models of MCPH1.
Highlights
MCPH1, or BRIT1, is often mutated in human primary microcephaly type 1, a neurodevelopmental disorder characterized by a smaller brain size at birth, due to its dysfunction in regulating the proliferation and self-renewal of neuroprogenitor cells
The MCPH1 protein exists in two major isoforms: the full-length MCPH1 (MCPH1-FL; 835aa) and the second one is expressed from an alternative transcript lacking the last six exons (MCPH1∆e9–14; 611aa)
MCPH1 contains three BRCT (BRCA C-terminal) domains, which were first described in BRCA proteins but can be found in many DNA damage response (DDR) proteins
Summary
To ensure the development of the unusually large human brain to its size and complexity, highly precise mechanisms must govern temporal-spatial processes of the neuroprogenitor cells (NPCs) and their derivatives for their proliferation and differentiation. The relationship between the axis of cell polarity and the orientation of the cleavage plane (which is orthogonal to the mitotic spindle) is critical in deciding whether the cells undergo a symmetric or an asymmetric division [14,15] According to this hypothesis, cell fate determinants are unequally distributed in the dividing parent cell. The continuous expansion of the list clearly demonstrates a high genetic heterogeneity of MCPH Many of these genes have been implicated in various molecular and cellular processes, which contribute to the etiology of MCPHs. Strikingly, the vast majority of them play a role in centrosome function and mitotic spindle alignment [21,22].
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