Rethinking the neural crest - a novel dynamic hypothesis of neural crest fate restriction

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All cell types in the body derive from stem or other precursor cells. These precursors are multipotent, having the flexibility to develop into any one of many types of working cells (e.g. neurons, blood or skin cells). A major problem in developmental biology is to understand how these flexible precursors make a specific choice of cell-type to adopt. The scale of the problem is illustrated by the fact that for one key exemplar, neural crest stem cells, there is still uncertainty about how the process works even after four decades of research - do fully multipotent cells 'jump' straight to a specific chosen fate, or do they go through a series of steps in which their options become more and more limited, until eventually they choose a single cell-type? These two models - Direct Fate Restriction (DFR) and Progressive Fate Restriction (PFR) - have each received support from different studies, but are conflicting. Although PFR is now the textbook view of neural crest development, a prominent paper studying mouse neural crest recently concluded firmly with a DFR interpretation. As a result of work done on an ongoing BBSRC grant studying neural crest stem cells in zebrafish embryos, we are proposing a revolutionary new view, which we believe reconciles these conflicts. We have been looking at the formation of pigment cell-types from the neural crest, as a model of neural crest development in general. Specifically, we have been looking at melanocytes (black pigment cells, well-known for their roles in skin and hair colour in humans, and giving rise to melanoma), and iridophores, a shiny silver cell-type that is prominent in most fishes. We see evidence for only some very broadly multipotent precursors, leading us to propose our novel Cyclical Fate Restriction model. We think that neural crest precursors are variable because they are highly dynamic, constantly changing. This view is consistent with, and reconciles, the conflicting data and interpretations in the field. Increasingly, stem cell biology is being explored using a mathematical modelling approach which has often given key insights into how they function. Surprisingly, perhaps, almost all this work has focused on 'binary choices', and so has ignored the possibilities of a DFR-type process. Even for PFR, modelling has not explored how binary choices might be interlinked to generate multiple diverse derivatives.In this project, we will test and explore our new Cyclical Fate Restriction model, using experimental studies and mathematical modelling to gain insight into how the process might work. A key experiment is to use a complementary technique to look at gene activity in thousands of neural crest cells, looking comprehensively at their cell-profiles so as to study the range of identifiable precursor states in the neural crest. We will then use a sensitive technique to look at such cell-types directly in the embryo. In parallel we will explore the mathematical basis for the three models, developing current models to describe PFR, and applying novel theoretical insights to stem cell biology to investigate the plausibility of both DFR and our novel Cyclical model. We will integrate the two approaches, experimentally investigating biological features relevant to the models, including direct assessment of the direction of change of progenitor cells, and quantitative investigation of the key fate specification signals in the neural crest.Together, these studies will test a revolutionary view of neural crest stem cell biology. Understanding these processes has implications well beyond the basic biology we are studying here. In particular, it is important in a medical context, in that this process of stem cells choosing between different cell-types is of fundamental importance to understanding the healthy body and how it goes wrong in ageing and in disease. It thus will shed light on the mechanisms underlying congenital diseases and cancer.