Wnt/PCP controls spreading of Wnt/β-catenin signals by cytonemes in vertebrates

Abstract

Signaling filopodia, termed cytonemes, are dynamic actin-based membrane structures that regulate the exchange of signaling molecules and their receptors within tissues. However, how cytoneme formation is regulated remains unclear. Here, we show that Wnt/planar cell polarity (PCP) autocrine signaling controls the emergence of cytonemes, and that cytonemes subsequently control paracrine Wnt/β-catenin signal activation. Upon binding of the Wnt family member Wnt8a, the receptor tyrosine kinase Ror2 becomes activated. Ror2/PCP signaling leads to the induction of cytonemes, which mediate the transport of Wnt8a to neighboring cells. In the Wnt-receiving cells, Wnt8a on cytonemes triggers Wnt/β-catenin-dependent gene transcription and proliferation. We show that cytoneme-based Wnt transport operates in diverse processes, including zebrafish development, murine intestinal crypt and human cancer organoids, demonstrating that Wnt transport by cytonemes and its control via the Ror2 pathway is highly conserved in vertebrates.

Wnt Signaling and Drug Resistance in Cancer

“…Some Wnts such as Wnt5a and Frizzleds are involved in the regulation of intracellular calcium levels and planar cell polarity (Kikuchi et al, 2012). Some Wnts can bind to receptor tyrosine kinases such as ROR2 and RYK to activate downstream signaling leading to, e.g., cytoneme extension (Mattes et al, 2018). Notably, one established effect of Wnt5a is antagonism of the canonical Wnt/b-catenin signaling (Ishitani et al, 2003;Topol et al, 2003;Mikels and Nusse, 2006).…”

<p>Cdc42 Promotes ADSC-Derived IPC Induction, Proliferation, And Insulin Secretion Via Wnt/β-Catenin Signaling</p>

“…Wnt signaling plays a crucial regulatory role in the development process and tissue homeostasis of multicellular organisms, including cell-specific differentiation, cell proliferation, morphogenesis, and tissue integrity maintenance. 21,22 Wnt signaling network is composed of several branches, classified as 1) the classical β-catenin-dependent Wnt pathway; 2) the βcatenin-independent Wnt/planar cell polarity (PCP) pathway; and 3) the non-classical Wnt/calcium pathway. 23 Wnt/β-catenin signaling is involved in the genesis of pancreatic islets and the proliferation of pancreatic β cells.…”

Wnt Signaling Drives Ectopic Gene Expression and Larval Arrest in the Absence of theCaenorhabditis elegansDREAM Repressor Complex

“…Of the five Wnt ligands, EGL-20 has most often been shown to interact with the Wnt/PCP pathway (Green et al 2008;Mentink et al 2018). In the intestine, the only documented role of Wnt/PCP signaling is for proper orientation of intestinal cells during intestinal morphogenesis (Asan et al 2016;Hoffmann et al 2010), but in other tissues Wnt/PCP signaling can help to regulate A-P fate specification (Ackley 2014;Antic et al 2010;He et al 2018;Mattes et al 2018;Mentink et al 2018). It is still unclear what role Wnt/PCP signaling plays in regulating gene expression and fate specification in the intestine.…”