Feb 3rd Science - Part II

Long overdue.... I know.

Nuclearized β- catenin (yellow/orange) in the 

vegetal pole of a sea urchin embryo, indicative 

of active cWnt signaling. (c) McClay, Duke.

Much of my work right now involves understanding how the environment can alter development and the resulting ecological consequences for larvae. This sort of developmental plasticity could be advantageous to rapidly responding to changing environments. However, it is important that much (really most) of developmental processes are insulated from environmental signals. This is especially true early in development when the basic cell types and overall patterning are specified. It wouldn't be advantageous for your future muscle cells to become gut, for example. So understanding when and why developmental programs are either receptive to environmental signals or refractory to (insulated from) them is essential to understanding how developmental defects arise and for current research trying to artificially mimic development in a dish.

Sethi et al, Science 2012 show a beautiful example of how two of the three basic cell types in most animals - endoderm (gives rise to the gut) and mesoderm (gives rise to muscles and other cell types) - are segregated from a common 'endomesoderm' state and become refractory to external signals. This segregation is NOT a single event but is a process and progression.

A cell-to-cell signaling event initiates the process. The localized nature of the signaling event is important because it allows only the future mesoderm to receive the initial signal.

As signals often do, this alters gene expression. So often we focus on what is turned on, but here, what is essential is what is turned off. By turning off a key early endomesoderm-state transcription factor in the future mesoderm, the resulting cascade of gene regulatory interactions allows the mesoderm-specific program to run and turns off another signal (a cWnt, see image) in the mesoderm. This carves out a new mesoderm territory.

Notch signaling suppression in mesoderm.

Endoderm's reinforcing loop. (c) Science

                                                                                                                            In the endoderm, the endomesoderm-state transcription factors continue to be expressed and drive the expresssion of the cWnt signaling molecule. The endoderm factors form a reinforcing loop with cWnt signaling driving transcription factors and those factors driving cWnt expression. Thus, by turning off gene expression in one territory but not in another one, two new states are created.

We're not done yet. If cWnt signaling is inappropriately received by the mesoderm, it will initiate the expression of endoderm genes. In order to prevent this, the initial cell-to-cell signal turns on a protein that can eliminate active cWnt signaling in the mesoderm by sequestering an essential co-factor. Now, the two states are insulated from one another.

Cell-fate specification, and development in general, is not just about turning things on. What gets turned off and prevented from being turned on (through insulation from 'outside' signaling) are just as important.

So for my purposes, I'm left wondering why and how some processes are left open to external signals. When is development robust and when is it plastic? Are there ways gene are connected (business jargon: gene regulatory network architectures) that make the process more robust? -- Sethi et al show reinforcing loops and insulation from signaling as possible mechanisms. Are there ways genes are connected that make the process more plastic? -- like in organ development with multiple, dynamic signaling inputs between multiple cell types? ... We're working on it...

Sethi, A.J., R.M. Wikramanayake, R.C. Angerer, R.C. Range, and L.M. Angerer. 2012. Sequential signaling crosstalk regulates endomesoderm segregation in sea urchin embryos. Science. v335:590-593. DOI: 10.1126/science.1212867 
(Images of gene regulatory networks from Sethi et al 2012, Science).