Lgr4 and Lgr5 drive the formation of long actin-rich cytoneme-like membrane protrusions

Abstract

Embryonic development and adult tissue homeostasis require precise information exchange between cells and their microenvironment to coordinate cell behavior. A specialized class of ultra-long actin-rich filopodia, termed cytonemes, provides one mechanism for this spatiotemporal regulation of extracellular cues. We provide here a mechanism whereby the stem-cell marker Lgr5, and its family member Lgr4, promote the formation of cytonemes. Lgr4-and Lgr5-induced cytonemes exceed lengths of 80 mm, are generated through stabilization of nascent filopodia from an underlying lamellipodial-like network and functionally provide a pipeline for the transit of signaling effectors. As proof-of-principle, we demonstrate that Lgr5-induced cytonemes act as conduits for cell signaling by demonstrating that the actin motor and filopodial cargo carrier protein myosin X (Myo10) and the G-protein-coupled receptor (GPCR) signaling effector b-arrestin-2 (Arrb2) transit into cytonemes. This work delineates a biological function for Lgr4 and Lgr5 and provides the rationale to fully investigate Lgr4 and Lgr5 function and cytonemes in mammalian stem cell and cancer stem cell behavior.

LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells

“…EMT has been proposed as a crucial process in tumor metastasis. Both cells at the tumor invasive front and circulating breast tumor cells express EMT markers (77,78), and inhibition of EMT impairs metastasis in mouse models (81). Among the transcription factors potentially driving EMT in breast cancer, we observed a significant decrease in SLUG and ZEB1 expression after LGR4 knockdown in vitro.…”

Tongue and Taste Organ Biology and Function: Homeostasis Maintained by Hedgehog Signaling

“…Recently, we demonstrated that vimentin-positive fibroblast cells remain within the stromal core of the FGP after Hh repression, in association with Hh-responding cells (38). Many of the vimentin-positive cells near the papilla basal lamina and epithelium have a migratory-like morphology, with numerous, long filopodia-like extensions that might be cytonemes or invadopodia (92). In other systems, both Shh-producing and responding cells extend long specialized filopodia that function in Shh signaling and trafficking Shh packaged in particles (93).…”

Drosophilaovarian germline stem cell cytocensor projections dynamically receive and attenuate BMP signaling

“…While signaling projections are common during development, it remains to be determined whether they are also frequently found in adult stem cells. However, in the murine gut, intestinal stem cells extend apical processes that reach in between neighbouring Paneth cells that constitute a key part of the intestinal stem cell niche (Barker et al, 2007) and Lgr4/5 has been shown drive formation of cytoneme-like projections in vitro (Snyder et al, 2015). It will be interesting to determine the role of these projections in stem cell signaling and whether cytocensors are found in other developmental contexts.…”