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

Kurosaka S, Leu NA, Zhang F, Bunte R, Saha S, Wang J, Guo C, He W, Kashina A - PLoS Genet. (2010)

Bottom Line: Recent studies of protein arginylation implicated this poorly understood posttranslational modification in the functioning of actin cytoskeleton and in cell migration in culture.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

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.

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Knockout of the arginyltransferase Ate1 in the mesenchymal cells results in a significant reduction in their migration speeds.(A) The first and the last frame of a time lapse series of a wild-type (WT) and Ate1 knockout (KO) fibroblast monolayer moving into the wound. See Video S3 and Video S4 for the corresponding time lapse series. Bar, 200 µm. (B) Quantification of the average migration speed in wild-type (WT) and Ate1 knockout (KO) cultures calculated from the time lapse series similar to the one shown in (A). In wild-type average migration speed was 39.97+/−4.90(SEM), n = 2; in the knockout the speed was almost 4 times slower at 11.34+/−1.32(SEM), n = 4.
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pgen-1000878-g005: Knockout of the arginyltransferase Ate1 in the mesenchymal cells results in a significant reduction in their migration speeds.(A) The first and the last frame of a time lapse series of a wild-type (WT) and Ate1 knockout (KO) fibroblast monolayer moving into the wound. See Video S3 and Video S4 for the corresponding time lapse series. Bar, 200 µm. (B) Quantification of the average migration speed in wild-type (WT) and Ate1 knockout (KO) cultures calculated from the time lapse series similar to the one shown in (A). In wild-type average migration speed was 39.97+/−4.90(SEM), n = 2; in the knockout the speed was almost 4 times slower at 11.34+/−1.32(SEM), n = 4.

Mentions: While individual Ate1 knockout cells during shorter stretches of time were capable of moving at speeds similar to wild-type (not shown), the migration speed of the Ate1 knockout cell monolayers over continuous periods of time was nearly 4 times slower than that of wild-type cells (average speed of 11.5 µm/h compared to 41.3 µm/h in wild-type) (Figure 5, Video S3 and Video S4). This difference constitutes a significant delay in the overall migration, and, when transferred to an in vivo environment of a developing embryo would be likely to create significant morphogenic defects.


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

Kurosaka S, Leu NA, Zhang F, Bunte R, Saha S, Wang J, Guo C, He W, Kashina A - PLoS Genet. (2010)

Knockout of the arginyltransferase Ate1 in the mesenchymal cells results in a significant reduction in their migration speeds.(A) The first and the last frame of a time lapse series of a wild-type (WT) and Ate1 knockout (KO) fibroblast monolayer moving into the wound. See Video S3 and Video S4 for the corresponding time lapse series. Bar, 200 µm. (B) Quantification of the average migration speed in wild-type (WT) and Ate1 knockout (KO) cultures calculated from the time lapse series similar to the one shown in (A). In wild-type average migration speed was 39.97+/−4.90(SEM), n = 2; in the knockout the speed was almost 4 times slower at 11.34+/−1.32(SEM), n = 4.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2837401&req=5

pgen-1000878-g005: Knockout of the arginyltransferase Ate1 in the mesenchymal cells results in a significant reduction in their migration speeds.(A) The first and the last frame of a time lapse series of a wild-type (WT) and Ate1 knockout (KO) fibroblast monolayer moving into the wound. See Video S3 and Video S4 for the corresponding time lapse series. Bar, 200 µm. (B) Quantification of the average migration speed in wild-type (WT) and Ate1 knockout (KO) cultures calculated from the time lapse series similar to the one shown in (A). In wild-type average migration speed was 39.97+/−4.90(SEM), n = 2; in the knockout the speed was almost 4 times slower at 11.34+/−1.32(SEM), n = 4.
Mentions: While individual Ate1 knockout cells during shorter stretches of time were capable of moving at speeds similar to wild-type (not shown), the migration speed of the Ate1 knockout cell monolayers over continuous periods of time was nearly 4 times slower than that of wild-type cells (average speed of 11.5 µm/h compared to 41.3 µm/h in wild-type) (Figure 5, Video S3 and Video S4). This difference constitutes a significant delay in the overall migration, and, when transferred to an in vivo environment of a developing embryo would be likely to create significant morphogenic defects.

Bottom Line: Recent studies of protein arginylation implicated this poorly understood posttranslational modification in the functioning of actin cytoskeleton and in cell migration in culture.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

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.

Show MeSH
Related in: MedlinePlus