| First Author | Lian G | Year | 2019 |
| Journal | Cereb Cortex | Volume | 29 |
| Issue | 5 | Pages | 1938-1952 |
| PubMed ID | 29659741 | Mgi Jnum | J:298070 |
| Mgi Id | MGI:6438332 | Doi | 10.1093/cercor/bhy073 |
| Citation | Lian G, et al. (2019) Formin 2 Regulates Lysosomal Degradation of Wnt-Associated beta-Catenin in Neural Progenitors. Cereb Cortex 29(5):1938-1952 |
| abstractText | Although neural progenitor proliferation along the ventricular zone is regulated by beta-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 beta-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 beta-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 beta-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 beta-catenin activation. Downstream, RhoA-activated Fmn2 promotes lysosomal degradation of Dvl2, leading to beta-catenin degradation. |
