Arginylation-dependent neural crest cell migration is essential for mouse development

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.
Author Summary Formation of many organs during development depends on the coordinated migration of individual cells and cell layers throughout the embryo. The majority of migrating cells originate from the neural crest lineage that gives rise to peripheral neurons, ganglia, pigment cells, and craniofacial structures, as well as parts of other organs in the body. Recent studies have implicated arginylation—a poorly understood protein modification—in the regulation of basic mechanisms that underlie cell migration. Here 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. We find that these mice die at or soon after birth and exhibit severe defects in the development of distinct neural crest-derived structures. Our findings uncover a previously unknown mechanism of the regulation of neural crest cell migration during development, and shed light on general principles of neural crest migration in vivo.