Although neural progenitor proliferation along the ventricular zone is regulated by β-catenin through Wnt signaling, the cytoskeletal mechanisms that regulate expression and localization of these proteins are not well understood. Our prior studies have shown that loss of the actin-binding Filamin A (FlnA) and actin-nucleating protein Formin 2 (Fmn2) impairs endocytosis of low-density-lipoprotein-receptor-related protein 6 (Lrp6), thereby disrupting β-catenin activation, resulting in decreased brain size. Here, we report that activated RhoA-GTPase disengages Fmn2 N- to C-terminal binding to promote Fmn2 activation and redistribution into lysosomal vesicles. Fmn2 colocalizes with β-catenin in lysosomes and promotes its degradation. Further, Fmn2 binds the E3 ligase Smurf2, enhances Smurf2-dependent ubiquitination, and degradation of Dishevelled-2 (Dvl2), thereby initiates β-catenin degradation. Finally, Fmn2 overexpression disrupts neuroepithelial integrity, neuronal migration, and proliferation-phenotypes in E13 mouse embryos, as seen with loss of Fmn2+FlnA function. Conversely, co-expression of Dvl2 with Fmn2 rescues the proliferation defect due to Fmn2 overexpression in mouse embryos. These findings suggest that there is a homeostatic feedback mechanism in the cytoskeletal-dependent regulation of neural proliferation within the cerebral cortex. Upstream, Fmn2 promotes proliferation by stabilizing the Lrp6 receptor, leading to β-catenin activation. Downstream, RhoA-activated Fmn2 promotes lysosomal degradation of Dvl2, leading to β-catenin degradation.
The ability of stem cells to differentiate into any desired cell type can make them an indispensable tool in COVID-19 modelling studies. Stem cells derived from patients with preexisting conditions or derived from vulnerable populations such as children, can also assist scientists in understanding the unique contributions of these diverse factors to variations in COVID-19 infection responses. Innovative approaches are urgently needed to adequately address the global impact of COVID-19. Stem cell based strategies offer such an approach.
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