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.
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Funding
Research reported in this publication was supported by an award from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number R01NS091220 to WYK and a grant from the National Research Foundation of Korea under Grant Number NRF-2019R1A2C1009006 to MK.
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MK, JJM, and WK conceived, designed, performed, and analyzed the experiments. MK performed and analyzed the majority of the imaging experiments. JJM performed and analyzed the majority of the behavior experiments. MK, JM, and WK wrote the paper. WK supervised the work.
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Mice were handled in accordance with the animal protocol approved by the Institutional Animal Care and Use Committees (IACUC) at the University of Nebraska Medical Center and Kent State University. All experimental procedures met National Institutes of Health guidelines for the care and use of laboratory animals.
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10571_2021_1088_MOESM1_ESM.pdf
Supplementary Fig. 1. Relative brain size in Macf1-cKO mice. Relative brain weights and sizes were examined in control and Macf1-cKO mice. Their brain weights and sizes were normalized by whole body weights. N= 5 mice for each condition. Statistical significance was determined by two-tailed Student?s t-test. Data are shown as relative changes versus controls. *p < 0.05, **p < 0.01. Supplementary Fig. 2. Abnormal callosal axon development in the Macf1-cKO corpus callosum. Nissl staining of rostral and caudal areas in the coronal brain sections from 2-month-old control and Macf1-cKO mice. Stars indicate the corpus callosum. Scale bars: 200?m. The third panels show the dotted rectangular areas in the middle panels. (PDF 506 kb)
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Ka, M., Moffat, J.J. & Kim, WY. MACF1, Involved in the 1p34.2p34.3 Microdeletion Syndrome, is Essential in Cortical Progenitor Polarity and Brain Integrity. Cell Mol Neurobiol 42, 2187–2204 (2022). https://doi.org/10.1007/s10571-021-01088-1
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DOI: https://doi.org/10.1007/s10571-021-01088-1