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Loss of CPAP in developing mouse brain and its functional implication for human primary microcephaly
Yi-Nan Lin1, Ying-Shan Lee1, Shu-Kuei Li1
1Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529 Taiwan.
Journal of Cell Science
|June 6, 2020
Summary
Conditional knockout of the CPAP gene in mice causes severe brain development defects, including microcephaly and apoptosis. Loss of p53 partially rescues these CPAP-related phenotypes in developing brains.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Primary microcephaly (MCPH) is a neurodevelopmental disorder linked to small brain size and intellectual disability.
- The CPAP (also known as CENPJ) gene is crucial for centriole biogenesis and has been associated with MCPH.
Purpose of the Study:
- To investigate the role of the Cpap gene in mouse brain development using a conditional knockout model.
- To elucidate the mechanisms underlying CPAP-associated microcephaly and its relationship with p53.
Main Methods:
- Generation of a conditional knockout allele for the mouse Cpap gene.
- Analysis of brain development in Cpap-deficient mice, including assessment of cell division, apoptosis, and cilia formation.
- Investigation of the interaction between Cpap and p53 in regulating radial glia progenitor survival.
Main Results:
- Conditional Cpap deletion in the central nervous system induced monopolar spindles and apoptosis in radial glia progenitors (RGPs).
- Loss of one p53 allele partially rescued apoptosis and resulted in microcephalic brains, while complete p53 removal rescued RGP death.
- Cpap deletion caused cilia loss, RGP mislocalization, disrupted junctional integrity, heterotopia, and cerebellar hypoplasia.
Conclusions:
- Complete loss of CPAP function leads to severe and complex developmental brain defects in mice.
- These findings offer new insights into the pathogenesis of primary microcephaly and highlight the interplay between CPAP and p53 in brain development.
