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Research: Interactions between signalling pathways

The patterning of cellular ensembles during embryonic development requires the coordinated activity of a number of signalling pathways. There are not many of these and their structure is very conserved: Wnt, Notch, Receptor Tyrosine Kinase (RTKs), Hh, TG/BMPs and Steroid Receptors.

Signalling pathways are usually viewed as devices for the linear transfer of information within the cell which converge at the level of their target genes or proteins. However, the precision and robustness of the processes they mediate jointly suggests that they interact at many different levels and that individual component elements of each pathway contribute to integrated information processing networks rather than to parallel processing units. The structural conservation of these pathways suggests the existence of large constraints in their functional organization.

Our studies of interaction between signalling pathways have focused on Notch and Wnt signalling. The reason is historical (and, as anything historical, accidental) but it may turn out to have a reason. Notch gets its name from the founder members of a family of single transmembrane receptors which can act as membrane tethered transcription factors. Wnt, on the othet hand, is an acronym for the two founding members of a family of signalling molecules. Wnt= Wingless + Int-1, the founding members of the family. Wingless is a Drosophila gene and the protooncogene Int-1 its mouse orthologue.

Over the years we have obtained substantial evidence for intricate functional interactions between elements of Notch and Wnt signalling. These studies indicate that these pathways form a single functional unit that processes information. This realization has led us to coin the term 'Wntch' for the interlocked functional module made up from these two signalling systems (for details see Hayward et al. 2008 Wnt/Notch signalling and information prcoessing during development. Development. 2008 135, 411-424).

Functional interactions between two well characterized signalling pathways named after the receptor for one, Notch, and a ligand for the other, Wingless, provide a good example of the operation of such networks. Notch and Wingless each have dedicated signalling pathways, and we have shown that interactions between their elements are used to modulate and balance their outputs during development. In addition we have observed that signalling through Notch and Wingless converges onto a third shared pathway, which serves to integrate their inputs.

Integration of Wnt and Notch signaling in animal development

The basis of the development of an organism is the coordination of two events: the generation of large number of different cells and their organization into spatiotemporal patterns which we call tissues and organs. The second process relies on the first and therefore, the mechanisms and processs that assign fates to cells have occupied and occupy large research efforts.

We have suggested (Martinez Arias and Hayward, 2006 Filtering transcriptional noise during development: concepts and mechanisms. Nature Rev Genet. 7, 34-44) that the process of cell fate assignment can be decomposed into two steps. One, an initial phase, in which cells are given the potential to adopt a particular fate, and two a stabilization fate in which the fate is consolidated in some (but not all) of the cell in which it has been initiated (see Fig ). This suggestion underpins the well established fact that during development cells have potentials and fates and that their potentials are bigger than their fates.

We have suggested that a process of cell fate assignation can be decomposed into two steps. One, an initial phase in which cells are given the potential to adopt a fate and two, a stablization phase in which the fate is consolidated in some (but not all) of the cells in which it has been initiated (see Figure 2). This underpins the well established fact that cells in development have potentials and fates and that their potentials are bigger than their fates.

A very common strategy during development is to initiate a cell fate in a larger cell population than that in which the fate will be implemented. The initiation step depends on interactions between instructive signals and the resident transcriptiona factors and results in a metastable state in which the fate is reversible. Afterwards the fate is implemented. The inset shows a classic example of this in the definition of Semsory Organ Precursors in the imaginal discs of Drosophila. The picture shows the expression of the Achaete protein in a cluster of cells. The large cells with high levels (blue arrows) will become the precursors and the expression of Achaete will be extinguished from the rest of the cells. Whilst the cells express Achaete, they can adopt the neural fate.

Here, there is a formal representation of the metastable state (pink) during a cell fate assignment. In that state, a cell has the option to adopt the fate or to return to the original state. In terms of gene expression this can be represented by the picture shown below. Notice that we imagine the metastable state to be associated with fluctuating gene expression.

We believe that at the molecular level it is possible to separate the two steps. This can be clearly seen in the development of the Peripheral Nervous System of Drosophila, where the spatial and temporal regulation of genes of the achaete/scute complex determines the pattern of sensory organ precursors (SOPs). Members of the ac/sc complex become expressed in clusters of cells with defined spatial coordinates from which precursors arise. Analysis of the regulation of the ac/sc complex has uncovered complex spatial and temporal elements that regulate each cluster separately but then, mutations in elements of the Notch and Wnt signaling pathways affect all clusters in a similar way. Normally only one or two cells in each cluster become SOP, but in the absence of Notch ALL cells in the cluster become SOPs. Conversely in the absence of Wingless (the Drosophila Wnt-1), none of the cells of the cluster becomes an SOP. Neither Notch nor Wnt mutants affect the initiation of the expression in the clusters. This suggests to us that within each cluster cells are measuring the relative levels and strengths of Wnt and Notch signaling to decide whether or not to become an SOP i.e. the relative levels of Wnt and Notch signaling determine the probability with which the cells adopt the fate (see Fig). Interestingly the precursors arise from the region of the cluster nearer to the source of Wingless. Thus, if Wnt>Notch, SOP fate otherwise no fate.

The pattern of the bristles (SOP elements) of the fly is determined by clusters of Achaete/Scute expression (disc on top) and each cluster corresponds to one or two bristles. The pattern of clusters emerges over time through the iteration of integrative processes in which signalling interacts with resident transcription factors to generate patterns, more accurately pre-patterns, which are used as substrates for new patterns. At a point, probably determined by the architecture of various promoters, the summation of those integrative events leads to the pattern of clusters.

On this basis we have suggested that GRNs can create transiently noisy patterns of expression of fate determining genes and that the integrated action of Wnt and Notch signaling tips the balance one way or another. In fact we believe that the outputs of GRNs are always noisy.

Over the years we have been characterizing the interactions between Wnt and Notch in Drosophila and recently we have been looking at the emerging information from other systems, particularly vertebrates. These observations have led us to suggest that the two pathways are integrated into a module that we chose to call Wntch, and which acts as a transistor in cell fate assignments. The transistor has a structure that allows it to filter and amplify signals that the cells receive from other sources, and in development it acts to eliminate the noise from the pattern and to generate the specific functional set of cell fates, patterns correctly.

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