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.

1p34.2p34.3 缺失综合征的特点是自闭症风险增加。微管肌动蛋白交联因子 1 ( MACF1)是该综合征的候选基因之一。然而，尚不清楚MACF1缺失如何与大脑发育和神经发育缺陷相关。在此，我们报告了发育中的小鼠大脑皮层中Macf1 的缺失，重点关注放射状胶质细胞极性和形态完整性，因为这些是大脑形成的关键因素。我们发现，在皮质发育过程中删除Macf1会导致双皮质/皮质下带异位以及皮质层压破坏。与对照细胞相比， Macf1缺失的放射状祖细胞显示出更高的增殖率，但未能将其限制在发育中大脑中定义的增殖区内。Macf1缺失的放射状祖细胞的过度增殖与细胞周期速度加快和重新进入有关。Macf1突变皮层中沿心尖室区域的微管稳定性和肌动蛋白聚合降低。相应地，径向胶质纤维与心尖和软脑膜表面之间存在断开。最后，我们观察到Macf1突变小鼠表现出社交缺陷和异常情绪行为。总之，这些结果表明 MACF1 通过促进神经胶质纤维稳定和极化，在皮质祖细胞增殖和定位中发挥关键作用。我们的研究结果可能有助于深入了解 1p34.2p34.3 缺失综合征的致病机制。