Rab21 regulates caveolin‐1‐mediated endocytic trafficking to promote immature neurite pruning

Abstract

Transmembrane proteins are internalized by clathrin‐ and caveolin‐dependent endocytosis. Both pathways converge on early endosomes and are thought to share the small GTPase Rab5 as common regulator. In contrast to this notion, we show here that the clathrin‐ and caveolin‐mediated endocytic pathways are differentially regulated. Rab5 and Rab21 localize to distinct populations of early endosomes in cortical neurons and preferentially regulate clathrin‐ and caveolin‐mediated pathways, respectively, suggesting heterogeneity in the early endosomes, rather than a converging point. Suppression of Rab21, but not Rab5, results in decreased plasma membrane localization and total protein levels of caveolin‐1, which perturbs immature neurite pruning of cortical neurons, an in vivo ‐specific step of neuronal maturation. Taken together, our data indicate that clathrin‐ and caveolin‐mediated endocytic pathways run in parallel in early endosomes, which show different molecular regulation and physiological function. image Rab21 and Rab5 localize to distinct populations of early endosomes and play different roles in endocytic trafficking and in vivo neuronal maturation, suggesting heterogeneity in the early endosomal system. Rab21 preferentially colocalizes with caveolin‐1 and regulates caveolin‐mediated endocytic pathways. Rab5 mainly regulates clathrin‐mediated endocytic pathways and rarely colocalizes with caveolin‐1 in cerebral cortical neurons. Rab21, but not Rab5, promotes immature neurite pruning of cortical neurons in a caveolin‐1‐dependent manner. Rab21 regulates the plasma membrane localization of caveolin‐1, which subsequently suppresses the lysosomal degradation of caveolin‐1.