LRP2 contributes to planar cell polarity-dependent coordination of motile cilia function.

Motile cilia are protruding organelles on specialized epithelia that beat in a synchronous fashion to propel extracellular fluids. Coordination and orientation of cilia beating on individual cells and across tissues is a complex process dependent on planar cell polarity (PCP) signaling. Asymmetric sorting of PCP pathway components, essential to establish planar polarity, involves trafficking along the endocytic path, but the underlying regulatory processes remain incompletely understood. Here, we identified the endocytic receptor LRP2 as regulator of PCP component trafficking in ependyma, a multi-ciliated cell type that is involved in facilitating flow of the cerebrospinal fluid in the brain ventricular system. Lack of receptor expression in gene-targeted mice results in a failure to sort PCP core proteins to the anterior or posterior cell side and, consequently, in the inability to coordinate cilia arrangement and to aligned beating (loss of rotational and translational polarity). LRP2 deficiency coincides with a failure to sort NHERF1, a cytoplasmic LRP2 adaptor to the anterior cell side. As NHERF1 is essential to translocate PCP core protein Vangl2 to the plasma membrane, these data suggest a molecular mechanism whereby LRP2 interacts with PCP components through NHERF1 to control their asymmetric sorting along the endocytic path. Taken together, our findings identified the endocytic receptor LRP2 as a novel regulator of endosomal trafficking of PCP proteins, ensuring their asymmetric partition and establishment of translational and rotational planar cell polarity in the ependyma.

Single-Cell Transcriptomics Characterizes Cell Types in the Subventricular Zone and Uncovers Molecular Defects Impairing Adult Neurogenesis.

Neural stem cells (NSCs) contribute to plasticity and repair of the adult brain. Niches harboring NSCs regulate stem cell self-renewal and differentiation. We used comprehensive and untargeted single-cell RNA profiling to generate a molecular cell atlas of the largest germinal region of the adult mouse brain, the subventricular zone (SVZ). We characterized >20 neural and non-neural cell types and gained insights into the dynamics of neurogenesis by predicting future cell states based on computational analysis of RNA kinetics. Furthermore, we applied our single-cell approach to document decreased numbers of NSCs, reduced proliferation activity of progenitors, and perturbations in Wnt and BMP signaling pathways in mice lacking LRP2, an endocytic receptor required for SVZ maintenance. Our data provide a valuable resource to study adult neurogenesis and a proof of principle for the power of single-cell RNA sequencing to elucidate neural cell-type-specific alterations in loss-of-function models.