Functions of microcephalin in neurogenesis and human brain evolution

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Abstract

Primary microcephaly is a brain growth disorder of which the main phenotypic hallmarks is a reduction of brain size with varying degrees of intellectual disability. MCPH1 is the first gene reported to cause primary microcephaly. Microcephalin (MCPH1), the encoded protein product, has been implicated in various cellular processes deregulation of which can negatively affects neurogenesis. In our review we will discuss the clinical cases of MCPH1 primary microcephaly and summarize the knowledge about the functions of MCPH1 employing animal models with mutations in various domains of MCPH1. We also pay special attention to the role of MCPH1 in in the evolution of the human brain.

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A. M. Yunusova

Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences

Author for correspondence.
Email: anastasiajunusova@gmail.com
Russian Federation, Novosibirsk

T. A. Shnaider

Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences

Email: anastasiajunusova@gmail.com
Russian Federation, Novosibirsk

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2. Fig. 1. Functions of microcephalin (MCPH1): 1) participates in DNA repair through chromatin decondensation (via the SWI/SNF complex), recruitment of repair factors (BRCA2 and RAD51), and by enhancing the amplification signal of the ATR signaling pathway due to interaction with TopBP1; 2) regulates telomere stability and, in case of telomere dysfunction, recruits DNA repair factors and promotes resolution of replication stress in telomeric regions; 3) in the interphase nucleus maintains three-dimensional organization of chromatin by inhibiting the interaction of condensin II complexes with chromatin; controls the cell cycle through regulation of Chk 1–Cdc 2 5b; 4) through interaction with E 2F 1 activates expression of proteins involved in DNA repair, cell cycle control, and apoptosis; 5) represses hTERT expression. The red crosses indicate the relationships that are disrupted upon MCPH1 depletion. The figure was created using the BioRender service (https://biorender.com).

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3. Fig. 2. Schematic structure of the MCPH1 gene and the location of mutations described in patients with microcephaly. Exons are indicated by black rectangles; Δ are exon deletions. Mutations highlighted in red were identified in the DECIPHER project database in patients with signs of microcephaly and growth retardation. The figure was created using the BioRender service (https://biorender.com).

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4. Fig. 3. Schematic arrangement of mutations and their phenotypic manifestation in transgenic mice with Mcph1 mutations. Triangles located in introns flank deleted exons in transgenic mouse lines. Triangles above introns indicate the integration site of the cassette for creating deletions. The figure was created using the BioRender service (https://biorender.com).

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5. Fig. 4. MCPH1 maintains the balance between symmetric and asymmetric division of neural progenitors. MCPH1 depletion (Mcph1–/–) results in a decrease in the centrosomal Chk1 pool and activation of Cdk1. This in turn causes a premature transition of the G2–M cell cycle phases, when maturation of the daughter centrosome is not yet complete. As a result, during mitosis, centrosomes have different potential for organizing microtubules, which causes spindle asymmetry. Symmetric division results in equal inheritance of proteins and both daughter cells retain proliferative potential. Asymmetric division results in unequal inheritance of apical proteins and differentiation of cells into neurons. Adapted from: Gruber et al., 2011. The figure was generated using the BioRender service (https://biorender.com).

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