Abstract
Coordinated cell migration during development is crucial for morphogenesis and largely relies on cells of the neural crest lineage that migrate over long distances to give rise to organs and tissues throughout the body. Recent studies of protein arginylation implicated this poorly understood posttranslational modification in the functioning of actin cytoskeleton and in cell migration in culture. Knockout of arginyltransferase (Ate1) in mice leads to embryonic lethality and severe heart defects that are reminiscent of cell migration–dependent phenotypes seen in other mouse models. To test the hypothesis that arginylation regulates cell migration during morphogenesis, we produced Wnt1-Cre Ate1 conditional knockout mice (Wnt1-Ate1), with Ate1 deletion in the neural crest cells driven by Wnt1 promoter. Wnt1-Ate1 mice die at birth and in the first 2–3 weeks after birth with severe breathing problems and with growth and behavioral retardation. Wnt1-Ate1 pups have prominent defects, including short palate and altered opening to the nasopharynx, and cranial defects that likely contribute to the abnormal breathing and early death. Analysis of neural crest cell movement patterns in situ and cell motility in culture shows an overall delay in the migration of Ate1 knockout cells that is likely regulated by intracellular mechanisms rather than extracellular signaling events. Taken together, our data suggest that arginylation plays a general role in the migration of the neural crest cells in development by regulating the molecular machinery that underlies cell migration through tissues and organs during morphogenesis.
Highlights
Coordinated cell migration during development is crucial for tissue and organ morphogenesis from early gastrulation to adulthood
All these phenotypes resemble the phenotypes seen in the mouse models with knockouts of various genes implicated in cell migration, leading to the hypothesis that the mechanisms underlying cell migration may be the primary targets for regulation by arginylation
We test the role of arginylation in neural crest cell migration during mouse development by constructing and examining a mouse model with arginylation-deficient neural crest cells
Summary
Coordinated cell migration during development is crucial for tissue and organ morphogenesis from early gastrulation to adulthood. Neural crest cells are of mesenchymal morphology and migrate from the trunk into different areas of the developing embryo These cells express a distinct subset of markers, including Wnt and others [1,2,3,4,5,6,7,8], at or before the onset of migration. Knockout of arginyltransferase (Ate1) in mice leads to embryonic lethality and severe cardiovascular defects, including abnormal heart septation, underdeveloped myocardium, and impaired angiogenesis [9] All these phenotypes resemble the phenotypes seen in the mouse models with knockouts of various genes implicated in cell migration, leading to the hypothesis that the mechanisms underlying cell migration may be the primary targets for regulation by arginylation (see [10] for review). All these data suggest that arginylation may be a general mechanism of the regulation of cell movement in different physiological events, the role of arginylation in directional cell migration in culture and during embryonic development has never been studied before
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