Formin 2 Regulates Lysosomal Degradation of Wnt-Associated β-Catenin in Neural Progenitors

Abstract

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.

Genome-wide DNA methylation profiles of autism spectrum disorder

“…In a report of psychiatric polygenic risk association analysis, FMN2 is found to be associated with brain function, including cognition, behavior, learning, memory, locomotion and sensory perception of sound (Lee et al , 2017). It is shown that loss of the FMN2 disrupts β-catenin activation and leads to decreased brain size (Lian et al , 2019). The single nucleotide polymorphism of FMN2 is found in repeated seizures (Ferland et al 2017).…”

Astrocytes control quiescent NSC reactivation via GPCR signaling-mediated F-actin remodeling

“…It will be of great interest to understand whether mammalian Mrtf also regulates neural stem cell proliferation. Consistent with the role of Drosophila Dia in NSC reactivation, mammalian Formin 2 activates the Wnt signaling--Catenin pathway to regulate neural stem cell proliferation during brain development (86). Variants of Formins also have been identified in human microcephaly patients (23,24,38).…”

The genetic basis of hydrocephalus: genes, pathways, mechanisms, and global impact

“…TRIM71 and SMARCC1 are expressed within the ventricles and epithelium of mice brains (determined via in situ hybridization) suggesting that a mutation within this gene locus can affect this region may lead to HC [ 8 ]. Mutations in FOXJ1 and FMN2 have been shown to alter neuroepithelial integrity and lead to HC in mice [ 56 , 57 ]. Mice harboring mutations in PTCH1 also display defects in ependymal cell integrity [ 58 ].…”