Editors' ChoiceCell Migration

Phactr4 Integrin Antagonism

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Sci. Signal.  10 Jan 2012:
Vol. 5, Issue 206, pp. ec12
DOI: 10.1126/scisignal.2002830

Development of the enteric nervous system requires a complex migration of enteric neural crest cells (ENCCs) from the foregut to the colon, with some solitary advance cells leading a chain of collectively migrating cells. Zhang et al. report that ENCC migration requires the phosphatase and actin regulator 4 (Phactr4), which binds to both actin and protein phosphatase 1 (PP1). Mice homozygous for the Phactr4humdy/humdy allele, which prevents Phactr4 from binding to PP1, showed disorganization and reduced numbers of ENCCs in the colon and intestinal blockage reminiscent of Hirschsprung disease (HSCR), a type of congenital megacolon in which patients lack enteric ganglia. Specification, differentiation, and proliferation of ENCCs were normal in Phactr4humdy/humdy mutant embryos, but a greater proportion of the mutant ENCCs migrated individually and with a more erratic path than those in wild-type (WT) embryos. In cultured gut explants, inhibiting PP1 with okadaic acid (OA) caused ENCC migration defects similar to those observed in Phactr4humdy/humdy mutants. Whereas WT mouse embryo fibroblasts (MEFs) migrated directionally in a wound-healing assay and had one large lamellipodium per cell, Phactr4humdy/humdy mutant MEFs moved erratically and had multiple small lamellipodia. Both endogenous Phactr4 and transgenically encoded Phactr4humdy/humdy colocalized in MEF lamellipodia with the actin-depolymerizing protein cofilin, which can be activated by PP1. The relative abundance of phosphorylated cofilin was increased in mutant MEFs and in OA-treated WT MEFs, suggesting that Phactr4 could act as a scaffold to bring PP1 and cofilin together. Cofilin activity can be repressed by integrin signaling through the small GTPase Rho and the Rho-associated kinase ROCK. Phactr4 colocalized with β1 integrin in MEF lamellipodia and negatively regulated integrin signaling through Rho and ROCK. Treatment with a pharmacological inhibitor of ROCK or a peptide that blocks integrin binding to its ligands restored collective migration and the single-lamellipodium phenotype to Phactr4humdy/humdy MEFs and rescued the migration defects in cultured mutant ENCCs. Thus, Phactr4 promotes directed migration by antagonizing β1 integrin signaling to promote the activity of cofilin. These findings not only identify a negative regulator of integrin signaling that could function in other contexts (there are four Phactr family members) but also may offer insight into cases of HSCR not attributable to previously characterized mutations.

Y. Zhang, T.-H. Kim, L. Niswander, Phactr4 regulates directional migration of enteric neural crest through PP1, integrin signaling, and cofilin activity. Genes Dev. 26, 69–81 (2012). [Abstract] [Full Text]

Z. Sun, R. Fässler, A firm grip does not always pay off: A new Phact(r) 4 integrin signaling. Genes Dev. 26, 1–5 (2012). [Abstract] [Full Text]

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