Cadherin EGF LAG seven-pass G-type receptor (Celsr) proteins 1-3 comprise a subgroup of adhesion GPCRs whose functions range from planar cell polarity (PCP) signaling to axon pathfinding and ciliogenesis. Like its Drosophila ortholog, Flamingo, mammalian Celsr1 is a core component of the PCP pathway, which, among other roles, is responsible for the coordinated alignment of hair follicles across the skin surface. Although the role of Celsr1 in epidermal planar polarity is well established, the contribution of the other major epidermally expressed Celsr protein, Celsr2, has not been investigated. Here, using two new CRISPR/Cas9-targeted Celsr1 and Celsr2 knockout mouse lines, we define the relative contributions of Celsr1 and Celsr2 to PCP establishment in the skin. We find that Celsr1 is the major Celsr family member involved in epidermal PCP. Removal of Celsr1 function alone abolishes PCP protein asymmetry and hair follicle polarization, whereas epidermal PCP is unaffected by loss of Celsr2. Further, elimination of both Celsr proteins only minimally enhances the Celsr1−/− phenotype. Using FRAP and junctional enrichment assays to measure differences in Celsr1 and Celsr2 adhesive interactions, we find that compared to Celsr1, which stably enriches at junctional interfaces, Celsr2 is much less efficiently recruited to and immobilized at junctions. As the two proteins seem equivalent in their ability to interact with core PCP proteins Vangl2 and Fz6, we suggest that perhaps differences in homophilic adhesion contribute to the differential involvement of Celsr1 and Celsr2 in epidermal PCP.
The kidney develops through elaboration of ureteric epithelial tubules (the future urinary collecting ducts), stroma, and nephron progenitors in the cap mesenchyme that surrounds each ureteric tip as they branch. Dynamic interactions between these tissues coordinate a balance between ureteric tip branching and nephron formation that sets nephron numbers for life, which impacts the probability of adult disease. How then is this balance achieved? Here we study the geometric and mechanical consequences of tubule tip crowding at the embryonic kidney surface and its effect on nephron formation. We find that kidney surface curvature reduces and tubule 'tip domains' pack more closely over developmental time. These together create a semi-crystalline geometry of tips at the kidney surface and a rigidity transition to more solid-like tissue properties at later developmental stages. New tips overcome mechanical resistance as they branch, expand, and displace close-packed neighbors, after which residual mechanical stress dissipates. This correlates with a changing nephrogenesis rate over the tip 'life-cycle'. To draw a causal link between the two, we mimic a mechanical transient in human iPSC-derived nephron progenitor organoids and find increased cell commitment to early nephron aggregates. The data suggest that temporal waves of mechanical stress within nephron progenitor populations could constitute a clock that synchronizes nephron formation and ureteric tubule duplication after E15. Ongoing efforts to understand the spatial and temporal regulation of nephron induction will clarify variation in nephron endowment between kidneys and advance engineered kidney tissues for regenerative medicine.
The planar cell polarity (PCP) pathway collectively orients thousands of cells with respect to a body axis to direct cellular behaviors that are essential for embryonic morphogenesis. Hair follicles of the murine epidermis provide a striking readout of PCP activity in their uniform alignment along the entire skin surface. Here, we characterize, from the molecular to tissue-scale, PCP establishment in the rosette fancy mouse, a natural variant with posterior-specific whorls in its fur, to understand how epidermal polarity is coordinated across the tissue. We find that embryonic hair follicles of rosette mutants emerge with reversed orientations specifically in the posterior region, creating a mirror image of epidermal polarity. The rosette trait is associated with a missense mutation in the core PCP gene Fzd6, which alters a consensus site for N-linked glycosylation and inhibits its membrane localization. Unexpectedly, this defect in Fzd6 trafficking, observed across the entire dorsal epidermis, does not interfere with the ability of other core PCP proteins to localize asymmetrically. Rather, the normally uniform axis of PCP asymmetry is disrupted and rotated in the posterior region such that polarity is reflected on either side of a transition zone. The result is a reversal of polarized cell movements that orient nascent follicles, specifically in the posterior of the embryo. Collectively, our multiscale analysis of epidermal polarity reveals PCP patterning can be regionally decoupled to produce the unique posterior whorls of the fancy rosette mouse.
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