LaFever, K. S. | bioRxiv Science

bioRxiv2020

A protease-initiated model of wound detection

Wounds trigger surrounding cells to initiate repair, but it is unclear how cells detect wounds. The first known wound response of epithelial cells is a dramatic increase in cytosolic calcium, which occurs within seconds, but it is not known what initiates this calcium response. Specifically, is there an instructive signal detected by cells surrounding wounds? Here we identify a signal transduction pathway in epithelial cells initiated by the G-protein coupled receptor Methuselah-like 10 (Mthl10) activated around wounds by its cytokine ligands, Growth-blocking peptides (Gbps). Gbps are present in unwounded tissue in latent form, requiring proteolytic activation for signaling. Multiple protease families can activate Gbps, suggesting it acts as a detector to signal the presence of several proteases. We present experimental and computational evidence that proteases released during cell lysis serve as the instructive signal from wounds, liberating Gbp ligands to diffuse to the Mthl10 receptors on epithelial cells and activate downstream release of calcium. Thus, the presence of a nearby wound is signaled by the activation of a Gbp protease detector, sensitive to multiple proteases released after cellular damage.

cell biology↗

bioRxiv2020

Extracellular spreading of Wingless is required for Drosophila oogenesis

Recent studies have investigated whether the Wnt family of extracellular ligands can signal at long range, spreading from their source and acting as morphogens, or whether they signal only in a juxtacrine manner to neighboring cells. The original evidence for long-range Wnt signaling arose from studies of Wg, a Drosophila Wnt protein, which patterns the wing disc over several cell diameters from a central source of Wg ligand. However, the requirement of long-range Wg for patterning was called into question when it was reported that replacing the secreted protein Wg with a membrane-tethered version, NRT-Wg, results in flies with normally patterned wings. We and others previously reported that Wg spreads in the ovary about 50 m or 5 cell diameters, from the cap cells to the follicle stem cells (FSCs) and that Wg stimulates FSC proliferation. We used the NRT-wg flies to analyze the consequence of tethering Wg to the cap cells. NRT-wg homozygous flies are sickly, but we found that hemizygous NRT-wg/null flies, carrying only one copy of tethered Wingless, were significantly healthier. Despite their overall improved health, these hemizygous flies displayed dramatic reductions in fertility and in FSC proliferation. Further, FSC proliferation was nearly undetectable when the wg locus was converted to NRT-wg only in adults, and the resulting germarium phenotype was consistent with a previously reported wg loss-of-function phenotype. We conclude that Wg protein spreads from its source cells in the germarium to promote FSC proliferation.

developmental biology↗