WDPCP

WDPCP is a planar cell polarity (PCP) effector that coordinates ciliogenesis and actin-based cell behavior by acting as a recruitment scaffold for septins (PMID:24302887). At the ciliary transition zone it is required to assemble Sept2, Nphp1, and Mks1, and its loss removes these components and impairs cilium formation (PMID:24302887); in human airway epithelium WDPCP similarly supports cilia number and length and Septin7 expression (PMID:28001338). In parallel, WDPCP localizes to the cytoplasmic actin cytoskeleton and focal adhesions where it binds and co-localizes with Sept2, so that its loss disrupts actin filament organization and focal contacts, abolishes membrane ruffling, and prevents establishment of cell polarity and directional migration — a function it executes independently of cilia (PMID:24302887). Through control of cortical septin localization it maintains basolateral membrane stability and balanced cortical tension via actomyosin (PMID:25436430). Beyond these structural roles, WDPCP is a positive regulator of Hedgehog signaling required for the proliferative and differentiation responses of skeletal progenitors (PMID:34225660), and it drives epithelial-mesenchymal transition and migration of epicardium-derived cells needed for coronary artery smooth muscle coverage (PMID:29487191). In epithelial and endothelial cells WDPCP signals through the MAPK/ERK axis to support mitochondrial biogenesis and cilia beating and to promote EMT and migration (PMID:33598458, PMID:39582775). The conserved residues D481/W482 are required for apical docking and for sustaining ciliogenesis and Hedgehog signaling, defining a structural determinant of WDPCP localization and function (PMID:41268724).

1. 2013 High

   Established WDPCP's dual molecular role by showing it is a septin-recruiting scaffold both at the ciliary transition zone and on the cytoplasmic actin cytoskeleton, defining how a single PCP effector links ciliogenesis to actin organization.

   Evidence Immunofluorescence localization, Co-IP, and loss-of-function phenotyping in a Wdpcp-deficient mouse model with cochlear epistasis

   PMID:24302887

   Open questions at the time

   • Mechanism by which WDPCP selects between transition-zone and actin/focal-adhesion pools not defined
   • Whether Sept2 binding is direct or bridged by other factors not resolved
   • Stoichiometry and structure of the WDPCP-septin assembly unknown
2. 2014 Medium

   Extended the actin role to tissue mechanics, showing WDPCP controls cortical septin localization to maintain basolateral membrane stability and cortical tension through actomyosin.

   Evidence In vivo 3D time-lapse imaging and pharmacological actomyosin manipulation in Xenopus epithelium

   PMID:25436430

   Open questions at the time

   • Single-lab, single-organism evidence
   • Direct molecular link between WDPCP and actomyosin regulators not established
   • Quantitative relationship between septin localization and tension not defined
3. 2017 Medium

   Confirmed WDPCP's ciliogenic requirement in human cells and linked it to a specific septin, showing knockdown reduces cilia and Septin7 expression in human sinonasal epithelium.

   Evidence siRNA knockdown in air-liquid interface human sinonasal epithelial cultures with cilia and Septin7 immunofluorescence

   PMID:28001338

   Open questions at the time

   • Whether Septin7 reduction is cause or consequence of cilia loss unresolved
   • Single-lab knockdown without rescue
   • Relationship to the Sept2 axis from mouse work not reconciled
4. 2018 High

   Placed WDPCP in a developmental signaling pathway by showing epicardium-specific deletion blocks EMT and EPDC migration required for coronary artery smooth muscle coverage.

   Evidence Epicardium-specific conditional Wdpcp knockout mice with EMT marker, migration, and histological readouts

   PMID:29487191

   Open questions at the time

   • Molecular effectors connecting WDPCP to EMT not identified in this study
   • Whether the EMT role depends on cilia or actin functions not separated
5. 2021 Medium

   Defined WDPCP as a positive regulator of Hedgehog signaling, showing its loss in skeletal progenitors abolishes Hh responsiveness and impairs chondro-/osteogenic differentiation.

   Evidence Prx1-Cre conditional Wdpcp knockout mice with in vitro Hh-stimulated differentiation assays

   PMID:34225660

   Open questions at the time

   • Whether the Hh defect is secondary to ciliary dysfunction not disentangled
   • Step in the Hh cascade affected by WDPCP unknown
   • Single-lab evidence
6. 2021 Medium

   Identified a signaling output for WDPCP in cilia function, showing knockdown impairs mitochondrial biogenesis and cilia beating via MAPK/ERK, with pharmacological rescue.

   Evidence siRNA knockdown in air-liquid interface cultures with U0126 inhibition and MAPK activation, mitochondrial and cilia beat frequency assays

   PMID:33598458

   Open questions at the time

   • Mechanism linking WDPCP to MAPK activation not defined
   • Whether mitochondrial effect is direct or downstream of ciliary defect unclear
   • Single-lab knockdown study
7. 2024 Medium

   Connected WDPCP/MAPK signaling to a downstream effector and a metabolic input, showing high leucine suppresses WDPCP to attenuate ERK signaling and impair endothelial EMT and migration via EMCN.

   Evidence WDPCP overexpression and knockdown in HCMECs with MAPK activator rescue, EMCN analysis, and high-leucine mouse model

   PMID:39582775

   Open questions at the time

   • Mechanism by which leucine suppresses WDPCP expression unknown
   • Whether EMCN is a direct WDPCP/MAPK target not established
   • Single-lab evidence
8. 2025 High

   Mapped a structural determinant of WDPCP function, showing conserved residues D481/W482 are required for apical docking and that their deletion abolishes localization, ciliogenesis, and Hh signaling.

   Evidence Structure-guided two-codon-deletion knock-in mouse with rescue experiments, localization, cilia, and Hh readouts, plus structure prediction

   PMID:41268724

   Open questions at the time

   • Experimental structure of WDPCP not determined
   • Identity of the apical docking partner recognized via D481/W482 unknown
   • Whether the same residues mediate the actin/septin functions not tested

• How WDPCP is partitioned between its transition-zone, cytoplasmic actin, and MAPK-signaling roles, and which direct partners couple it to Hedgehog and EMT outputs, remains unresolved.
• No unifying mechanism links the septin-scaffolding and MAPK-signaling functions
• Direct molecular partner mediating apical docking unidentified
• Whether Hh and EMT roles are cilium-dependent or cilium-independent not fully separated