Dorsal root ganglion development - analysis of sox10 function using novel transgenic and mutant resources in zebrafish

In normal development it is vital that cells make decisions about what type of cell to become. The peripheral nervous system consists of a series of clusters of cells (ganglia). These clusters contain cells of two types, neurons, and support cells (glia). To function correctly the ganglia must have appropriate numbers of both neurons and glia. Thus, cells must be allocated to each of these cell-types in the appropriate numbers. For one set of ganglia, the sensory ganglia, we know of several influences of cell fate. One is a protein that controls the activity of many genes - the set of genes that are activated determine whether that cell will be a neuron or a glial cell. The other is a set of proteins that mediate communication between adjacent cells, allowing co-ordination of their fate choices. Understanding how cells of developing ganglia co-ordinate these two influences is a key problem in understanding normal development. We have recently isolated a unique mutant in the former protein that appears to result in a defect in the function of the second system. Our proposal would allow us to test our ideas of how these influences are co-ordinated to generate ganglia.

Understanding of how stem cells generate varied derivative cell-types is of fundamental importance both for our understanding of development and if we are to consider using such stem cells medically. The neural crest generates very diverse derivative fates, including most peripheral neural fates, and is widely considered to consist of one or more stem cell types. In peripheral ganglia such as dorsal root ganglia (DRGs), fate specification of both neurons and glia must occur in close spatial proximity. Several factors involved in this process have been identified, including neurogenin, notch-delta signalling and sox10, but little is understood of how they interact. Our studies of zebrafish sox10 mutant alleles, including a preliminary characterisation of a novel allele with a neurogenic sensory neuron phenotype, suggest a model to integrate these known influences. In contrast to published studies in mice, and in accordance with our fate Specification model of sox10 function in neural crest, our data is consistent with a direct role for sox10 in sensory neuron specification. In this proposal we will perform a series of direct and indirect tests of this model, which gives specific predictions distinct from those of an alternative precocious differentiation model based on the recent studies of the role of sox10 in sympathetic ganglial development.