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PMID:22215812

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Citation

Zhang, Y, Kim, TH and Niswander, L (2012) Phactr4 regulates directional migration of enteric neural crest through PP1, integrin signaling, and cofilin activity. Genes Dev. 26:69-81

Abstract

Hirschsprung disease (HSCR) is caused by a reduction of enteric neural crest cells (ENCCs) in the gut and gastrointestinal blockage. Knowledge of the genetics underlying HSCR is incomplete, particularly genes that control cellular behaviors of ENCC migration. Here we report a novel regulator of ENCC migration in mice. Disruption of the Phactr4 gene causes an embryonic gastrointestinal defect due to colon hypoganglionosis, which resembles human HSCR. Time-lapse imaging of ENCCs within the embryonic gut demonstrates a collective cell migration defect. Mutant ENCCs show undirected cellular protrusions and disrupted directional and chain migration. Phactr4 acts cell-autonomously in ENCCs and colocalizes with integrin and cofilin at cell protrusions. Mechanistically, we show that Phactr4 negatively regulates integrin signaling through the RHO/ROCK pathway and coordinates protein phosphatase 1 (PP1) with cofilin activity to regulate cytoskeletal dynamics. Strikingly, lamellipodia formation and in vivo ENCC chain migration defects are rescued by inhibition of ROCK or integrin function. Our results demonstrate a previously unknown pathway in ENCC collective migration in vivo and provide new candidate genes for human genetic studies of HSCR.

Links

PubMed PMC3258968 Online version:10.1101/gad.179283.111

Keywords

Actin Depolymerizing Factors/metabolism; Animals; Cell Movement; Cells, Cultured; Enteric Nervous System/cytology; Enteric Nervous System/embryology; Gastrointestinal Tract/cytology; Gastrointestinal Tract/embryology; Integrins/physiology; Mice; Neural Crest/cytology; Neural Crest/embryology; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Protein Phosphatase 1/genetics; Protein Phosphatase 1/metabolism; Signal Transduction

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:PHAR4

involved_in

GO:0030036: actin cytoskeleton organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PHAR4

involved_in

GO:0001755: neural crest cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PHAR4

located_in

GO:0030027: lamellipodium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PHAR4

involved_in

GO:0007266: Rho protein signal transduction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PHAR4

involved_in

GO:2001045: negative regulation of integrin-mediated signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PHAR4

involved_in

GO:0048484: enteric nervous system development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PHAR4

enables

GO:0072542: protein phosphatase activator activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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