Polycystin‐1 Controls Cell Cycle Kinetics, Cell Cycle Exit, and Differentiation of Neural Progenitor Cells

In neocortical neurogenesis, neural progenitor cells (NPCs) give rise to diverse types of neurons. During this process, the balance between proliferation and differentiation, cell division mode determination, and cell fate specification are all intimately linked to the cell cycle of the NPCs. The cell cycle length hypothesis states that G1-phase lengthening switches NPCs from proliferative to neurogenic divisions. Meanwhile, however, the importance of S-phase shortening in differentiating NPCs emerges. Mutations in the polycystin-1 (PC1)- and polycystin-2 (PC2)-encoding genes are causative for the development of autosomal dominant polycystic kidney disease (ADPKD), a prominent feature of which is unbalanced cell proliferation. Here, we examine the impact of PC1 and PC2 on cell cycle kinetics, cell cycle exit, and the neuronal differentiation of NPCs. Loss-of-function analysis and cell-based assays demonstrate that NPCs with reduced PC1 expression exhibit a longer cell cycle with an increased S-phase duration. The cell cycle exit and the neuronal differentiation of these cells are significantly delayed. A strong tendency towards similar phenotypes is observed when reducing PC2 expression in NPCs. Thus, decreasing PC1 expression expands the pool of slowly cycling NPCs. These results highlight the significance of S-phase shortening in neurogenesis and may contribute to a better understanding of ADPKD pathophysiology.