Wave at the frogs – they’re waving at you

Perhaps, like me, you’ve been microinjecting Xenopus embryos for so long that you start seeing strange things – maybe that they’re waving at you.  But perhaps that’s not so crazy as it sounds.  In a letter to Nature this week (you can also view this talk), Jeremy Chang and James Ferrell Jr. from Stanford discuss the evidence that contraction waves form along the surface of fertilised eggs, suggesting a mechanism for coordination of spatial information at the very earliest points of embryonic development.

Xenopus laevis eggs are large – greater than 1 mm in diameter.  Therefore you might think that the cell cycle is slow in these large, unwieldy cells, requiring longer diffusion times for molecules to move around the cell to regulate cytokinesis and cell division.  However, as anyone who has worked with these frog embryos is well aware, the early cell divisions are incredibly rapid – the first cell cycle is 90 minutes at room temperature, followed by a dozen rapid synchronous cell divisions every 30 minutes.  How is this rapid division related to the molecules that control it?

The authors suggest a mechanism revolving around maintaining Cdk1 activity, using positive and negative feedback loops that generate a bistable environment – essentially, causing waves of Cdk1 activity to propagate through the cell.  They refer to these “trigger waves” – which are waves caused by areas of high local (mitotic) activity causing nearby regions to flip from interphase to mitotic activity and therefore propagating a wave that spreads outwards.  Subsequent activation of APC/C and thus cyclin degradation would then trigger waves of mitotic exit, and if cyclin synthesis follows, a cycle is generated.

The authors discuss and propose this model, then looked for experimental evidence to test the hypothesis in the well-established extract systems that Xenopus laevis eggs provide.  By adding sperm chromatin and fluorescent nuclear-localising protein as reporters of mitosis to frog egg extracts, they were able to observe propagation of waves – there are videos attached to the paper you should watch – showing movement of the extract from interphase, to mitosis and back again. They link this directly back to the activity of Cdk1 by manipulating the feedback mechanisms of Wee1 and Myt1.

They then looked at intact fertilized eggs.  If the centrosome, an area of high Cdc25 and therefore Cdk1 activity, initiates trigger waves they could be observed as waves of contraction on the surface of the embryo, moving from the pigmented animal hemisphere at the top to the vegetal bottom.  The paper gives images illustrating this. Cdk1 is a kinase, which adds phosphate groups to proteins to affect their activity, and it is thought the changes in pigment are caused by the fibres being modified as the waves of activity spread out.

Of course, this isn’t just a frog thing (it’s never just a frog thing) – frogs provide an extreme example of the scale of the problem but it’s likely that this is how cell division occurs in embryo development and all situations where cells are dividing.  It’s a nice example of Xenopus laevis providing an excellent model for biophysical studies and models of the propagation of signals in cell division.

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