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Updated: May 2, 2026
Imaging Centrosomes in Fly Testes
Published on: September 20, 2013
Microcephaly-associated genes asp and Sas4 influence chromatin organization and nuclear lamina structure in
Degisew Yinur Mengistu1, Marta Marzullo1,2, Claudia Pellacani1,2
1Department of Biology and Biotechnologies 'C. Darwin', Sapienza University of Rome, Rome 00185, Italy.
Abstract:
Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by reduced brain size and intellectual disability. Mutations in over 30 genes, nearly half linked to centrosome biogenesis or microtubule (MT) dynamics, highlight spindle defects in disease aetiology, yet these alone do not fully explain MCPH. Here, we show that the Drosophila orthologs of ASPM/MCPH5 (asp) and CENPJ/MCPH6 (Sas4) contribute to safeguard nuclear architecture and chromatin organization during brain development. Loss of either gene perturbs MT organization and centromere clustering, leading to reduced Lamin and HP1α levels, and to deformed nuclear lamina. Mutants also display a global reduction in heterochromatin-associated histone marks, H3K9me2/3 and H3K27me3, along with an increase in the euchromatin-associated mark H3K4me3 and elevated DNA damage with delayed repair. Notably, inhibiting demethylases with methylstat restores H3K9me3 and nuclear morphology. These findings suggest a previously unreported role for centrosome proteins in regulating chromatin organization, providing new insights into the mechanisms underlying MCPH pathogenesis.
Insights
Autosomal recessive primary microcephaly (MCPH) is linked to centrosome proteins ASPM and Sas4, which are crucial for nuclear architecture and chromatin organization during brain development. Disrupting these proteins leads to DNA damage and altered histone marks, offering new insights into MCPH pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder causing reduced brain size and intellectual disability.
- Mutations in over 30 genes, many related to centrosome function and microtubule dynamics, are implicated in MCPH.
- Existing knowledge suggests spindle defects contribute to MCPH, but do not fully explain the disease's mechanisms.
Purpose of the Study:
- To investigate the role of Drosophila orthologs of ASPM/MCPH5 (asp) and CENPJ/MCPH6 (Sas4) in nuclear architecture and chromatin organization.
- To elucidate the molecular mechanisms underlying MCPH pathogenesis related to centrosome protein function.
Main Methods:
- Utilized Drosophila melanogaster as a model organism to study gene function.
- Analyzed effects of asp and Sas4 gene disruption on microtubule organization, centromere clustering, nuclear lamina integrity, and histone modifications.
- Assessed DNA damage and repair dynamics in mutant models.
Main Results:
- Loss of asp or Sas4 function perturbs microtubule organization and centromere clustering.
- Mutants exhibit reduced Lamin and HP1α levels, leading to deformed nuclear lamina.
- Global reduction in heterochromatin marks (H3K9me2/3, H3K27me3) and increase in euchromatin mark (H3K4me3) observed.
- Elevated DNA damage with delayed repair was detected in mutant brains.
- Inhibition of demethylases with Methylstat partially restored H3K9me3 levels and nuclear morphology.
Conclusions:
- Centrosome proteins ASPM and Sas4 play a critical role in maintaining nuclear architecture and chromatin organization during brain development.
- Perturbations in these centrosome proteins lead to epigenetic alterations and DNA damage, contributing to MCPH pathogenesis.
- Findings reveal a novel function of centrosome proteins in regulating chromatin organization, expanding our understanding of MCPH mechanisms.
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