Research Article: Arginylation-Dependent Neural Crest Cell Migration Is Essential for Mouse Development

Date Published: March 12, 2010

Publisher: Public Library of Science

Author(s): Satoshi Kurosaka, N. Adrian Leu, Fangliang Zhang, Ralph Bunte, Sougata Saha, Junling Wang, Caiying Guo, Wei He, Anna Kashina, Marianne Bronner-Fraser

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.

Partial Text: Coordinated cell migration during development is crucial for tissue and organ morphogenesis from early gastrulation to adulthood. The largest cell populations that are capable of long-range migration at different developmental stages originate from the neural crest lineage. 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 Wnt1 and others [1]–[8], at or before the onset of migration.

Our data show that knockout of the arginyltransferase Ate1 in the cells of the neural crest lineage results in multiple morphogenic defects and perinatal lethality in mice. It has been previously shown that complete Ate1 knockout in mice leads to embryonic lethality and defects in cardiovascular development and angiogenesis [9] that are reminiscent of the defects seen in mouse models with knockout of genes implicated in cell adhesion and migration during embryogenesis [10]. Here we show for the first time that Ate1 deletion in the migratory subpopulations of the neural crest cells leads to delayed development and reduced size of the neural crest-derived organs and tissues, suggesting that Ate1-dependent migration of the neural crest cells is essential for normal embryogenesis.