Caveolin-1 Promotes Early Neuronal Maturation via Caveolae-Independent Trafficking of N-Cadherin and L1

Abstract

SummaryAxon specification is morphologically reproducible in vitro, whereas dendrite formation differs in vitro and in vivo. Cortical neurons initially develop immature neurites, but in vivo these are eliminated concurrently with the formation of a leading process, the future dendrite. However, the molecular mechanisms underlying these neuronal maturation events remain unclear. Here we show that caveolin-1, a major component of caveolae that are never observed in neurons, regulates in vivo-specific steps of neuronal maturation. Caveolin-1 is predominantly expressed in immature cortical neurons and regulates clathrin-independent endocytosis. In vivo knockdown of caveolin-1 disturbs immature neurite pruning, leading process elongation, and subsequent neuronal migration. Importantly, N-cadherin and L1, which are required for immature neurite formation, undergo caveolin-1-mediated endocytosis to eliminate immature neurites. Collectively, our findings indicate that caveolin-1 regulates N-cadherin and L1 trafficking independent of caveolae, which contributes to spatiotemporally restricted cellular events; immature neurite pruning and leading process elongation during early neuronal maturation.

Human antigen R-regulated mRNA metabolism promotes the cell motility of migrating mouse neurons

“…The Arp2/3 complex is an actin nucleator that produces branched actin networks, and is essential for the maintenance of radial glial cell (RGC) polarity and organization (Wang et al, 2016). Caveolin 1 regulates clathrin-independent endocytosis and elongation of the leading process (Shikanai et al, 2018). Cofilin disassembles actin filaments, and is negatively regulated by the CDK5-p27 pathway.…”

Molecular Mechanisms of Cadherin Function During Cortical Migration

“…Despite neurons not displaying caveolae, caveolin 1 is expressed in the developing cortex, particularly in the neurites of multipolar cells in the intermediate zone, where it is involved in clathrin-independent endocytosis. Downregulation of caveolin 1 increases the ratio of surface to total levels of two adhesion proteins: CDH2 and L1CAM, while decreasing their levels in early endosomes, suggesting that caveolin 1 is needed for their internalization (Shikanai et al, 2018). Neurons deficient in caveolin 1 acquire bipolar morphology, but their leading processes are shorter and more branched than in control neurons, with increased immature neurites that are retained even after leading process formation (Figures 1,1a).…”

Non-caveolar caveolins – duties outside the caves

“…Shikanai et al have demonstrated that CAV1 is strongly expressed in immature neurons of the mouse embryonic cerebral cortex (Shikanai et al, 2018), where CAV1 distributes between the PM and endosomes. Primary cortical neurons with reduced CAV1 expression show impaired glycosphingolipid internalization.…”

“…In contrast to caveolins immobilized within caveolae, studies in PC3 cells demonstrate that caveolin scaffolds diffuse rapidly, being internalized through diverse non-caveolar pathways into early endosomes (Hill et al, 2008;Moon et al, 2014). Endocytosis of caveolins is active in other systems with low cavin levels, such as in neurons and C. elegans, regulating trafficking of specific lipids and proteins (Scheidel et al, 2018;Shikanai et al, 2018). On endosomes, caveolin could organize signaling platforms (Jung et al, 2018).…”