A protein that points cells in the right direction
In animals, the stretching of skin tissue during the growth of an embryo requires the unique signals of the CDC-42 GTPase protein. It directs the movement of migrating cells.
Tissues in an embryo change shape through a process called intercalation — meaning 'to insert between layers.' One special form of intercalation allows a sheet of tissue cells to wedge between two neighboring cell layers, narrowing the original tissue from side to side and, but at the same time, elongating it front to back. As cells begin to intercalate, they form highly polarized tips that lead their migration.
In this study, the authors investigated the role of a protein called CDC-42 GTPase through the process of intercalation. They used skin from the back of the roundworm C. elegans for testing.
The CDC-42 protein is known to help cells determine front from back — up from down, in other words, individual cell polarity.
The protein CDC-42 GTPase is highly conserved, or maintained, across animal species. It is also a highly regulated (turned off) protein that controls the actin cytoskeleton — made up of microtubules, actin filaments, and intermediate filaments. These structures give the cell shape and help organize it's parts. In addition, they provide the basis for cell movement and division.
Scientists have had difficulty studying CDC-42 in embryos because disrupting its function interferes with early development. To cope with this, researchers devised a form of the protein that is always active or negatively dominates other forms of CDC-42. The CDC-42 protein they created is found only in skin cells and only at elevated temperatures.
Experiments show that CDC-42 is involved in both formation and orientation of cell tips during cell rearrangement. They also identified other proteins that function in causing intercalation — known cell polarity proteins: PAR-3 and PAR-6, and the cell surface receptor, VAB-1. CDC-42 also contributes to the intercalation process by helping orient the extending cell tip.
Jeff Hardin PhD, senior author, comments, "The orderly choreography that these rearranging cells engage in is really quite remarkable, but until now we've been unable to study it in detail. We are excited to study the earlier events that lead these cells to become polarized, and the subsequent steps that allow them to carry out this amazing cellular dance."
These results demonstrate the importance of CDC-42 as a key regulator of cell polarity and for guiding cells in the right direction during cell migration.
Additionally, the study identifies a novel pathway regulating one of the ubiquitous processes occurring in animal development and organ formation — using proteins conserved from worms to humans.
The result of the experiments was written by Elise Walck-Shannon PhD, and Jeff Hardin PhD, both of the Department of Zoology, in the University of Wisconsin, Madison, USA — along with their colleagues — in the November 18 edition of PLOS Genetics.
Cell intercalation is a highly directed cell rearrangement that is essential for animal morphogenesis. As such, intercalation requires orchestration of cell polarity across the plane of the tissue. CDC-42 is a Rho family GTPase with key functions in cell polarity, yet its role during epithelial intercalation has not been established because its roles early in embryogenesis have historically made it difficult to study. To circumvent these early requirements, in this paper we use tissue-specific and conditional loss-of-function approaches to identify a role for CDC-42 during intercalation of the Caenorhabditis elegans dorsal embryonic epidermis. CDC-42 activity is enriched in the medial tips of intercalating cells, which extend as cells migrate past one another. Moreover, CDC-42 is involved in both the efficient formation and orientation of cell tips during cell rearrangement. Using conditional loss-of-function we also show that the PAR complex functions in tip formation and orientation. Additionally, we find that the sole C. elegans Eph receptor, VAB-1, functions during this process in an Ephrin-independent manner. Using epistasis analysis, we find that vab-1 lies in the same genetic pathway as cdc-42 and is responsible for polarizing CDC-42 activity to the medial tip. Together, these data establish a previously uncharacterized role for polarized CDC-42, in conjunction with PAR-6, PAR-3 and an Eph receptor, during epithelial intercalation.
Citation: Walck-Shannon E, Lucas B, Chin-Sang I, Reiner D, Kumfer K, Cochran H, et al. (2016) CDC-42 Orients Cell Migration during Epithelial Intercalation in the Caenorhabditis elegans Epidermis. PLoS Genet 12(11): e1006415. doi:10.1371/journal.pgen.1006415
Funding: EWS and JH are supported by National Institutes of Health grant GM R01GM058038. ICS is funded by the Natural Sciences and Engineering Research Council of Canada (NSERC 249779) and the Canadian Institutes for Health Research (CIHR 130541). DR is supported by NIH grant GM R01GM085309. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
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Nov 22, 2016 Fetal Timeline Maternal Timeline News News Archive
A heat map of the activity of the protein CDC-42 in skin cells of an embryonic C. elegans.
The cells are undergoing an orderly change in position known as dorsal intercalation.
BRIGHT Yellow and Red indicate high activity at the tip of each cell (indicated by arrows).
Image Credit: Elise Walck-Shannon and Jeff Hardin, Univeristy of Wisconsin-Madison