Pvr receptor tyrosine kinase promotes tissue closure by coordinating corpse removal and epidermal zippering

Abstract

A leading cause of human birth defects is the incomplete fusion of tissues, often manifested in the palate, heart, or neural tube. To investigate the molecular control of tissue fusion, embryonic dorsal closure and pupal thorax closure in Drosophila are useful experimental models. We find that Pvr mutants have defects in dorsal midline closure with incomplete amnioserosa internalization and epidermal zippering, as well as cardia bifida. These defects are relatively mild in comparison to those seen with other signaling mutants such as the JNK pathway, and we demonstrate that JNK signaling is not perturbed by altering Pvr receptor tyrosine kinase activity. Rather, modulation of Pvr levels in the ectoderm has an impact on PIP3 membrane accumulation consistent with a link to PI3K signal transduction. Polarized PI3K activity influences protrusive activity from the epidermal leading edge and protrusion area changes in accord with Pvr signaling intensity, providing a possible mechanism to explain Pvr mutant phenotypes. Tissue specific rescue experiments indicate a partial requirement in epithelial tissue, but confirm the essential role of Pvr in the hemocytes for embryonic survival. Taken together, we argue that inefficient removal of the internalizing amnioserosa tissue by mutant hemocytes coupled with impaired midline zippering of mutant epithelium creates a situation in some embryos where dorsal midline closure is incomplete. Based on these observations, we suggest that efferocytosis (corpse clearance) could contribute to proper tissue closure and thus may underlie some congenital birth defects.

Pvr receptor tyrosine kinase signaling promotes post-embryonic morphogenesis, and survival of glia and neural progenitor cells in Drosophila

“…My data show that Pvr loss-of-function impairs cortex glia morphogenesis and survival. This is consistent with previous studies showing that Pvr signaling is required for trophic support and morphogenesis in other cell types (Brückner et al, 2004;Garlena et al, 2015;Parsons and Foley, 2013). I found that loss of Pvf-Pvr function decreased PI3K signaling in cortex glia, that loss of PI3K pathway components partially phenocopies Pvf-Pvr loss of function, and that restoration of PI3K signaling in glia partially rescued the effects of Pvr knockdown.…”

“…In Drosophila, Pvf-Pvr signaling activates PI3K, Ras-Map kinase, Rho-Rac and Cadherin pathways (Brückner et al, 2004;Cho et al, 2002;Duchek et al, 2001;Garlena et al, 2015;McDonald et al, 2003). Genetic and cell biological approaches were used to determine which of these pathways are required for cortex glia development downstream of Pvf-Pvr.…”

A Luciferase-fragment Complementation Assay to Detect Lipid Droplet-associated Protein-Protein Interactions

“…In the absence of OA Hmu, Cpr, and Gp93 localize in a reticular pattern. Pvr is enriched at the plasma membrane, as reported previously (72,73), and on intracellular membranes. The localization of Gp93 and Pvr does not change with OA addition, whereas Cpr and Hmu are now found in the vicinity of LDs.…”

Non-apoptotic function of Drosophila caspase activation in epithelial thorax closure and wound healing

“…Given that previous works have regarded Drosophila thorax closure as a model of general epithelial wound closure because of the distinctive commonalities (Garlena et al, 2015;Martín-Blanco and Knust, 2001;Zeitlinger and Bohmann, 1999), we examined wound closure of pupal nota using a multi-photon laser scanning confocal microscope. Notably, cells with activated caspase 3 have been also detected around wounded sites.…”