A biological clutch drives cell movements during embryogenesis

Apical constriction is a major mechanism in driving cell shape changes during key developmental events, including gastrulation, formation of the basic germ layers, as well as neural tube closure in vertebrates. Apical constriction is thought to be triggered by contraction of a cytoskeletal network, composed of actin filaments and myosin motor proteins (actomyosin). Here, we show that actomyosin contraction takes place even before cell shape changes are initiated, and that cell shape changes are only later coupled to actomyosin contractions. Furthermore, we identified key proteins that are essential for this coupling to take place. These proteins belong to two groups. First, we identified adherens junction proteins that bind cells to each other and to the actomyosin network. Second, we identified components of the Rac signaling pathway known to regulate cytoskeletal dynamics. Our study suggests a biological clutch-like mechanism that acts to couple cytoskeletal dynamics to cell movements.

HFSP Long-Term Fellows Gidi Shemer and Bob Goldstein and colleagues
authored on Mon, 19 March 2012

Cells move, and they move a LOT. They move throughout life (e.g. during wound healing), but cell movements started in your body even before you were born. The first movements took place when you were a very young embryo, when precursors of your gut moved inward, shaping what used to be a simple ball of cells into an embryo with three basic germ layers. This process is called gastrulation and it is the initial step in a complex set of events defined as morphogenesis. Some cell movements involve single cells, but in many cases, sheets of cells are moving in concert. Scientists have been fascinated with cell movement and have put a lot of effort in trying to understand two key issues. First, how cell movements are regulated by extrinsic cues, and second, how cells actually move.

Figure: Gut precursors (pseudo-colored in purple) move inward during embryogenesis in wild type embryos and then divide (left panel). In double mutants lacking cadherin (a component of the adherens junctions), and Rac, the gut precursors fail to move and divide on the surface (right panel).

One of the major mechanisms that drive sheets of cells to move in a timely manner is apical constriction. The driving force behind apical constriction is the contraction of a network of actin filaments that generates tension to shrink the apical side of the cell. The actin contraction requires activity of a motor protein called myosin II. In other words, actomyosin contraction serves as an engine that drives cell shape changes. In a sheet of epithelial cells that are adhered to each other, the shrinking of the apical surface of a few cells results in movement of the entire epithelial sheet.

In this paper we used gastrulation in the nematode Caenorhabditis elegans as a model to further investigate apical constriction. To date, scientists believed that the trigger for apical constriction is the initiation of actomyosin contraction. To our surprise, we found that the actomyosin network contracts even before cell shape changes occur. At first, these contractions occur without substantial shrinking of apical surfaces. Over time, the contractions become progressively linked to cell shape changes, and the apical surface of cells begins to shrink in concert with the dynamic actomyosin contractions.

In many ways, the cells behave quite similarly to a car with a stick shift. One must start the engine of the car, but that’s not enough. Only after the clutch becomes engaged, the force from the engine is transmitted to the wheels. In the cells, there is a period of slippage between the engine (the actomyosin network) and the wheels (the apical surface). Only after engagement of a potential molecular clutch, apical constriction occurs and cells gastrulate. Following this discovery, Dr. Minna Roh-Johnson, the first author of this paper tested early gastrulation events in the fly Drosophila melanoganster, only to find a similar scenario.

So, what is this molecular clutch composed of?

To start to answer this question we performed a genetic screen for genes that are required for gut precursor cells to gastrulate, and particularly, for genes that are necessary for coupling between apical constriction and actomyosin dynamic contractions. Our screen yielded two groups of genes that act partially redundantly. The first group, not surprisingly, is composed of cadherins and catenins, genes encoding components of the adherens junctions that “glue” cells together and serve as a linkage to the actin network. The second group consists of components of the Rac signaling pathway, a pathway that was known to be involved in cell migration, but via other mechanisms. When mutant embryos were deficient of genes from both these groups, the actomyosin network contracted normally, but there was no coupling of the actomyosin engine to cell shape changes, and as a result the cells failed to migrate, and stayed on the embryonic surface (see figure). 

The significance of this work is not only in identifying a new aspect of apical constriction and new molecular entities that take part in this event. As mentioned above, scientists are interested to learn how cell migration is regulated. Our findings suggest that scientists should now focus not only on how actomyosin contractions are initiated, but also on how the molecular clutch becomes engaged in response to extrinsic cues.  

Reference

Triggering a Cell Shape Change by Exploiting Preexisting Actomyosin Contractions. *Roh-Johnson M., *Shemer G., Higgins CD., McClellan JH., Werts AD., Tulu US., Gao L., Betzig E., Kiehart DP., Goldstein B. Science 9 March 2012: Vol. 335 no. 6073 pp. 1232-1235. * These authors contributed equally to this work.

Other references

Embryonic Clutch Control. Razzell W. and Martin P. Science 9 March 2012: 1181-1182.

Pubmed link