Hox regulatory networks and neuronal diversity

Our studies in chick and mouse embryos have provided evidence that Hox factors regulate the expression of genes selectively expressed by different motor neuron subtypes. Using genetic and biochemical approaches we are further exploring the mechanisms by which Hox proteins contribute to the diversification of motor neuron identities.

What are the mechanisms that restrict Hox gene function to motor neurons?

Hox proteins are broadly expressed in the embryo but have specific functions in motor neurons, suggesting the requirement for additional factors to “gate” the actions of Hox proteins in specific cell types. Studies in Drosophila have demonstrated that Forkhead (Fox) transcription factors can act as Hox cofactors. Our studies indicate that a vertebrate Fox protein, FoxP1, is a contextual cofactor for Hox proteins in the specification of motor neuron identities. We are exploring potential interactions of FoxP1 and Hox proteins on specific genes by performing chromatin immunoprecipitation (ChIP) assays using neurons isolated from ES cell-derived motor neurons.

What determines the activator and repressor functions of Hox proteins in motor neurons?

Our studies indicate that Hox proteins have distinct transcriptional activator and repressor functions in the specification of motor neuron subtypes. Hox repressor function establishes mutually exclusive domains of Hox gene expression whereas Hox activator function positively regulates motor neuron specific genes. We hypothesize that the distinct transcriptional outputs of Hox proteins are mediated through interactions with cofactors such as Pbx and Meis homeodomain proteins. We are testing this possibility using gain and loss of function assays in chick and mouse.