A negative modulatory role for rho and rho-associated kinase signaling in delamination of neural crest cells

Maya Groysman, Irit Shoval, Chaya Kalcheim*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

Background. Neural crest progenitors arise as epithelial cells and then undergo a process of epithelial to mesenchymal transition that precedes the generation of cellular motility and subsequent migration. We aim at understanding the underlying molecular network. Along this line, possible roles of Rho GTPases that act as molecular switches to control a variety of signal transduction pathways remain virtually unexplored, as are putative interactions between Rho proteins and additional known components of this cascade. Results. We investigated the role of Rho/Rock signaling in neural crest delamination. Active RhoA and RhoB are expressed in the membrane of epithelial progenitors and are downregulated upon delamination. In vivo loss-of-function of RhoA or RhoB or of overall Rho signaling by C3 transferase enhanced and/or triggered premature crest delamination yet had no effect on cell specification. Consistently, treatment of explanted neural primordia with membrane-permeable C3 or with the Rock inhibitor Y27632 both accelerated and enhanced crest emigration without affecting cell proliferation. These treatments altered neural crest morphology by reducing stress fibers, focal adhesions and downregulating membrane-bound N-cadherin. Reciprocally, activation of endogenous Rho by lysophosphatidic acid inhibited emigration while enhancing the above. Since delamination is triggered by BMP and requires G1/S transition, we examined their relationship with Rho. Blocking Rho/Rock function rescued crest emigration upon treatment with noggin or with the G1/S inhibitor mimosine. In the latter condition, cells emigrated while arrested at G1. Conversely, BMP4 was unable to rescue cell emigration when endogenous Rho activity was enhanced by lysophosphatidic acid. Conclusion. Rho-GTPases, through Rock, act downstream of BMP and of G1/S transition to negatively regulate crest delamination by modifying cytoskeleton assembly and intercellular adhesion.

Original languageAmerican English
Article number27
JournalNeural Development
Volume3
Issue number1
DOIs
StatePublished - 2008

Bibliographical note

Funding Information:
We thank Alexander Bershadsky and all members of our group for valuable discussions. We are indebted to Yi Zheng, G Prendergast, K Aktories, S Yonemura and A Ludwig for reagents. Anti-vinculin and a RhoB antibody were obtained from the Developmental Studies Hybridoma Bank. This work was supported by grants from DFG (SFB 488), Israel Cancer Research Fund (ICRF), Israel Science Foundation (ISF), March of Dimes, and EEU 6th Framework program Network of Excellence MYORES to CK.

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