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Genes & Dev. 26 (1): 69-81

Copyright © 2012 by Cold Spring Harbor Laboratory Press.

Phactr4 regulates directional migration of enteric neural crest through PP1, integrin signaling, and cofilin activity

Ying Zhang1, Tae-Hee Kim1,2,, and Lee Niswander3

Howard Hughes Medical Institute, Department of Pediatrics, Graduate Program in Cell Biology, Stem Cells, and Development, Children's Hospital Colorado, University of Colorado, Aurora, Colorado 80045, USA

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.

Key Words: directional cell migration • enteric neural crest cell • Hirschsprung disease • Phactr4 • PP1 • β1 integrin • cofilin

Received for publication September 18, 2011. Accepted for publication November 16, 2011.


1 These authors contributed equally to this work.

2 Present address: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, D720 44 Binney Street, Boston, MA 02115.

3 Corresponding author.

E-mail Lee.Niswander{at}ucdenver.edu.

Supplemental material is available for this article.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.179283.111.


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