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A Src-Tks5 pathway is required for neural crest cell migration during embryonic development.

In the adult organism, cell migration is required for physiological processes such as angiogenesis and immune surveillance, as well as pathological events such as tumor metastasis. The adaptor protein and Src substrate Tks5 is necessary for cancer cell migration through extracellular matrix in vitro and tumorigenicity in vivo. However, a role for Tks5 during embryonic development, where cell migration is essential, has not been examined. We used morpholinos to reduce Tks5 expression in zebrafish embryos, and observed developmental defects, most prominently in neural crest-derived tissues such as craniofacial structures and pigmentation. The Tks5 morphant phenotype was rescued by expression of mammalian Tks5, but not by a variant of Tks5 in which the Src phosphorylation sites have been mutated. We further evaluated the role of Tks5 in neural crest cells and neural crest-derived tissues and found that loss of Tks5 impaired their ventral migration. Inhibition of Src family kinases also led to abnormal ventral patterning of neural crest cells and their derivatives. We confirmed that these effects were likely to be cell autonomous by shRNA-mediated knockdown of Tks5 in a murine neural crest stem cell line. Tks5 was required for neural crest cell migration in vitro, and both Src and Tks5 were required for the formation of actin-rich structures with similarity to podosomes. Additionally, we observed that neural crest cells formed Src-Tks5-dependent cell protrusions in 3-D culture conditions and in vivo. These results reveal an important and novel role for the Src-Tks5 pathway in neural crest cell migration during embryonic development. Furthermore, our data suggests that this pathway regulates neural crest cell migration through the generation of actin-rich pro-migratory structures, implying that similar mechanisms are used to control cell migration during embryogenesis and cancer metastasis.

Pubmed ID: 21799874

Authors

  • Murphy DA
  • Diaz B
  • Bromann PA
  • Tsai JH
  • Kawakami Y
  • Maurer J
  • Stewart RA
  • Izpis├║a-Belmonte JC
  • Courtneidge SA

Journal

PloS one

Publication Data

July 29, 2011

Associated Grants

  • Agency: NCI NIH HHS, Id: P30 CA030199
  • Agency: PHS HHS, Id: R0O-NSO5860I
  • Agency: NCI NIH HHS, Id: T32 CA121938
  • Agency: NCI NIH HHS, Id: T32 CA121949

Mesh Terms

  • Actins
  • Animals
  • Cell Movement
  • Extracellular Matrix
  • Humans
  • Mice
  • Neural Crest
  • Phosphoproteins
  • Zebrafish
  • src-Family Kinases