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

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.