Specific subcellular localization drives the different functions of CDC42 isoforms during migration

The small G-protein CDC42 is an evolutionary conserved polarity protein and a key regulator of numerous polarized cell functions, including directed cell migration. In vertebrates, alternative splicing gives rise to two CDC42 proteins; the ubiquitously expressed isoform (CDC42u) and the brain isoform (CDC42b), whose specific role are not fully elucidated. The two isoforms only differ in their carboxy-terminal sequence, which includes the CAAX motif essential for CDC42 interaction with membrane. Here we show that these divergent sequences do not directly affect CDC42 ability to interact with its binding partners, but rather indirectly influence CDC42-mediated signaling by controlling the distinct subcellular localization of the two isoforms. In astrocytes and neural precursors, which naturally express both variants, CDC42u is mainly cytosolic and associates with the leading edge plasma membrane of migrating cells, whereas CDC42b mainly localizes to intracellular membrane compartments. During directed persistent migration CDC42u alone fulfills the polarity function while CDC42b embodies the major isoform regulating endocytosis. Both CDC42 isoforms act in concert by contributing their specific functions to promote chemotaxis of neural precursors, demonstrating that the expression pattern of the two isoforms is decisive for the tissue specific behavior of cells. ### Competing Interest Statement The authors have declared no competing interest.