title: Requisite role for Nck adaptors in cardiovascular development, endothelial-to-mesenchymal transition, and directed cell migration.
abstract: Development of the cardiovascular system is critically dependent on the ability of endothelial cells (ECs) to reorganize their intracellular actin architecture to facilitate migration, adhesion, and morphogenesis. Nck family cytoskeletal adaptors function as key mediators of actin dynamics in numerous cell types, though their role in EC biology remains largely unexplored. Here, we demonstrate an essential requirement for Nck within ECs. Mouse embryos lacking endothelial Nck1/2 expression develop extensive angiogenic defects that result in lethality at about embryonic day 10. Mutant embryos show immature vascular networks, with decreased vessel branching, aberrant perivascular cell recruitment, and reduced cardiac trabeculation. Strikingly, embryos deficient in endothelial Nck also fail to undergo the endothelial-to-mesenchymal transition (EnMT) required for cardiac valve morphogenesis, with loss of Nck disrupting expression of major EnMT markers, as well as suppressing mesenchymal outgrowth. Furthermore, we show that Nck-null ECs are unable to migrate downstream of vascular endothelial growth factor and angiopoietin-1, and they exhibit profound perturbations in cytoskeletal patterning, with disorganized cellular projections, impaired focal adhesion turnover, and disrupted actin-based signaling. Our collective findings thereby reveal a crucial role for Nck as a master regulator within the endothelium to control actin cytoskeleton organization, vascular network remodeling, and EnMT during cardiovascular development.
authors.affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.
authors.forename: Derek L
authors.initials: DL
authors.lastname: Clouthier
authors.affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.
authors.forename: Cameron N
authors.initials: CN
authors.lastname: Harris
authors.affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Harris
authors.affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Martin
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Mira C
authors.initials: MC
authors.lastname: Puri
authors.affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada jonesmcb@uoguelph.ca.
authors.forename: Nina
authors.initials: N
authors.lastname: Jones
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D018376:Cardiovascular Abnormalities / Q000196:embryology* / Q000235:genetics; D002319:Cardiovascular System / Q000196:embryology* / Q000378:metabolism; D002465:Cell Movement; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D017353:Gene Deletion; D051379:Mice; D008822:Mice, Transgenic; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C078332:Nck protein; D015513:Oncogene Proteins