Proteomics Analysis Identifies Orthologs of Human Chitinase-Like Proteins as Inducers of Tube Morphogenesis Defects inDrosophila melanogaster

Abstract

Elevated levels of human chitinase-like proteins (CLPs) are associated with numerous chronic inflammatory diseases and several cancers, often correlating with poor prognosis. Nevertheless, there is scant knowledge of their function. The CLPs normally mediate immune responses and wound healing and, when upregulated, they can promote disease progression by remodeling tissue, activating signaling cascades, stimulating proliferation and migration, and by regulating adhesion. We identified Imaginal disc growth factors (Idgfs), orthologs of human CLPs CHI3L1, CHI3L2, and OVGP1, in a proteomics analysis designed to discover factors that regulate tube morphogenesis in a model of tube formation. We implemented a novel approach that uses magnetic beads to isolate a small population of specialized ovarian cells, cells that nonautonomously regulate morphogenesis of epithelial tubes that form and secrete eggshell structures called dorsal appendages (DAs). Differential mass spectrometry analysis of these cells detected elevated levels of four of the six Idgf family members (Idgf1, Idgf2, Idgf4, and Idgf6) in flies mutant for (), which encodes a transcription factor and is a known regulator of DA-tube morphogenesis. We show that, during oogenesis, dysregulation of Idgfs (either gain or loss of function) disrupts the formation of the DA tubes. Previous studies demonstrate roles for Idgfs in innate immunity, wound healing, and cell proliferation and motility in cell culture. Here, we identify a novel role for Idgfs in both normal and aberrant tubulogenesis processes.

The indispensable contribution of s38 protein to ovarian-eggshell morphogenesis in Drosophila melanogaster

“…If so, the RNAi-mediated reduction of s38-protein content below a certain threshold can sensitize choriogenesis to stochastic variation in morphogenetic events and also disable or weaken negative-feedback-loop’s strength, leading to the diverse dysmorphias obtained and the different s38 -gene transcription activities observed between dysmorphic follicles carrying short or comparatively longer dorsal appendages. Interestingly, a similar type of incomplete penetrance has been recently described, suggesting a role of Idgfs (Imaginal disc growth factors) in the stochastic variation regarding coordination and timing of events during dorsal-appendages morphogenesis 50 .…”

The Trithorax group protein dMLL3/4 instructs the assembly of the zygotic genome at fertilization

“…The mammalian ortholog of IDGF4 is OVGP1, also known as oviductal glycoprotein 1 [37]. We observed that the dMLL3/4-regulated glycosyl hydrolase IDGF4 has a mitogenic effect on the early embryo.…”

“…We observed that the dMLL3/4-regulated glycosyl hydrolase IDGF4 has a mitogenic effect on the early embryo. The mammalian ortholog of IDGF4 is OVGP1, also known as oviductal glycoprotein 1 [37]. OVGP1 localizes to the oviduct-the site of mammalian fertilization-where it has been shown to be a component of the extracellular matrix of ovulated oocytes and early embryos [50,51].…”

“…IDGF4 is one of the six members of the IDGF family of glycosyl hydrolases [35,37]. IDGFs are required for insulin-dependent cell proliferation, polarization, and motility.…”

Detecting New Allies: Modifier Screen Identifies a Genetic Interaction BetweenImaginal disc growth factor 3andcombover, a Rho-kinase Substrate, During Dorsal Appendage Tube Formation inDrosophila

“…Lowering the expression of Idgf4, Idgf5, or Idgf6 ameliorates the bwk mutant phenotype, suggesting they are part of the bwk signaling pathway that regulates dorsal appendage formation. Up-regulating only a single member of this family, e.g., Idgf3, is sufficient to produce a phenotype similar to the bwk mutant ( Figure 1D) (Zimmerman et al 2017).…”