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Published on: April 14, 2017
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.
Abstract:
Primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by small brain size with mental retardation. CPAP (also known as CENPJ), a known microcephaly-associated gene, plays a key role in centriole biogenesis. Here, we generated a previously unreported conditional knockout allele in the mouse Cpap gene. Our results showed that conditional Cpap deletion in the central nervous system preferentially induces formation of monopolar spindles in radial glia progenitors (RGPs) at around embryonic day 14.5 and causes robust apoptosis that severely disrupts embryonic brains. Interestingly, microcephalic brains with reduced apoptosis are detected in conditional Cpap gene-deleted mice that lose only one allele of p53 (also known as Trp53), while simultaneous removal of p53 and Cpap rescues RGP death. Furthermore, Cpap deletion leads to cilia loss, RGP mislocalization, junctional integrity disruption, massive heterotopia and severe cerebellar hypoplasia. Together, these findings indicate that complete CPAP loss leads to severe and complex phenotypes in developing mouse brain, and provide new insights into the causes of MCPH.
Insights
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.
