MACF1, Involved in the 1p34.2p34.3 Microdeletion Syndrome, is Essential in Cortical Progenitor Polarity and Brain
Minhan Ka1, Jeffrey J Moffat2, Woo-Yang Kim3
1Research Center for Substance Abuse Pharmacology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
Abstract:
1p34.2p34.3 deletion syndrome is characterized by an increased risk for autism. Microtubule Actin Crosslinking Factor 1 (MACF1) is one candidate gene for this syndrome. It is unclear, however, how MACF1 deletion is linked to brain development and neurodevelopmental deficits. Here we report on Macf1 deletion in the developing mouse cerebral cortex, focusing on radial glia polarity and morphological integrity, as these are critical factors in brain formation. We found that deleting Macf1 during cortical development resulted in double cortex/subcortical band heterotopia as well as disrupted cortical lamination. Macf1-deleted radial progenitors showed increased proliferation rates compared to control cells but failed to remain confined within their defined proliferation zone in the developing brain. The overproliferation of Macf1-deleted radial progenitors was associated with elevated cell cycle speed and re-entry. Microtubule stability and actin polymerization along the apical ventricular area were decreased in the Macf1 mutant cortex. Correspondingly, there was a disconnection between radial glial fibers and the apical and pial surfaces. Finally, we observed that Macf1-mutant mice exhibited social deficits and aberrant emotional behaviors. Together, these results suggest that MACF1 plays a critical role in cortical progenitor proliferation and localization by promoting glial fiber stabilization and polarization. Our findings may provide insights into the pathogenic mechanism underlying the 1p34.2p34.3 deletion syndrome.
Insights
Microtubule Actin Crosslinking Factor 1 (MACF1) deletion disrupts mouse brain development, causing heterotopia and social deficits. This finding offers insights into 1p34.2p34.3 deletion syndrome and autism risk.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- 1p34.2p34.3 deletion syndrome increases autism risk.
- Microtubule Actin Crosslinking Factor 1 (MACF1) is a candidate gene for this syndrome.
- The role of MACF1 in brain development and neurodevelopmental deficits remains unclear.
Purpose of the Study:
- Investigate the function of MACF1 in the developing mouse cerebral cortex.
- Determine how MACF1 deletion impacts radial glia polarity and morphological integrity.
- Elucidate the mechanisms linking MACF1 to neurodevelopmental deficits.
Main Methods:
- Generated Macf1 deletion in the developing mouse cerebral cortex.
- Analyzed radial glia polarity, proliferation, and migration.
- Assessed microtubule stability and actin polymerization.
- Evaluated cortical lamination and brain morphology.
- Behavioral testing in Macf1-mutant mice (social and emotional behaviors).
Main Results:
- Macf1 deletion caused double cortex/subcortical band heterotopia and disrupted cortical lamination.
- Macf1-deleted radial progenitors exhibited increased proliferation, faster cell cycle re-entry, and failed to remain confined.
- Reduced microtubule stability and actin polymerization were observed in Macf1-mutant cortices.
- Disconnection between radial glial fibers and brain surfaces occurred.
- Macf1-mutant mice displayed social deficits and aberrant emotional behaviors.
Conclusions:
- MACF1 is critical for cortical progenitor proliferation and localization.
- MACF1 promotes radial glial fiber stabilization and polarization during brain development.
- These findings provide insights into the pathogenesis of 1p34.2p34.3 deletion syndrome and associated neurodevelopmental deficits.
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