title: The receptor tyrosine kinase Pvr 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 in 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 the 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 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 whereby dorsal midline closure is incomplete. Based on these observations, we suggest that efferocytosis (corpse clearance) could contribute to proper tissue closure and thus might underlie some congenital birth defects.
authors: Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: Rebecca A
authors: RA
authors: Garlena
authors: Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: Ashley L
authors: AL
authors: Lennox
authors: Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: Lewis R
authors: LR
authors: Baker
authors: Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: Trish E
authors: TE
authors: Parsons
authors: Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: Seth M
authors: SM
authors: Weinberg
authors: Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA stronach@pitt.edu.
authors: Beth E
authors: BE
authors: Stronach
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D001837:Body Weights and Measures; D057899:Cytophagocytosis / Q000502:physiology*; D004330:Drosophila / Q000196:embryology*; D029721:Drosophila Proteins / Q000378:metabolism*; D004817:Epidermis / Q000196:embryology*; D006652:Histological Techniques; D007091:Image Processing, Computer-Assisted; D018613:Microscopy, Confocal; D009024:Morphogenesis / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; C438368:Pvr protein, Drosophila; D020794:Receptor Protein-Tyrosine Kinases
keywords: Cell removal; Dorsal closure; Drosophila; Jun kinase; Morphometric analysis; PIP3; Pvr; Receptor tyrosine kinase; Thorax closure