The Role of SoxE Transcription Factors in Neural Crest Cell Specialization

Abstract Neurocristopathies are a class of syndromes that are predominately characterized by malformations in the craniofacial complex. These defects are caused by aberrant development of the neural crest, a stem cell population unique to vertebrates. One distinctive feature of the neural crest is their ability to give rise to both ectomesenchymal (bone/cartilage) and non-ectomesenchymal (melanocytes and peripheral neurons/glia) derivatives. SoxE transcription factors play important roles in both the formation and the diversification of the neural crest. All three SoxE factors (Sox8, Sox9, and Sox10) function redundantly to promote neural crest formation. Interestingly, individual SoxE factors direct the differentiation of the neural crest into distinct lineages. Sox9 promotes chondrogenesis while Sox10 supports both the melanocyte and peripheral neuron/glial fates. An outstanding question is how these highly similar SoxE factors lead to neural crest specialization. This proposal utilizes omics-based approaches, gain and loss of function experiments, and Sox9-Sox10 chimera constructs to assess how and when SoxE-mediated neural crest specialization occurs. Furthermore, mutations in SOX9 and SOX10 are causative for Campomelic dysplasia and Waardenburg syndrome, respectively. The syndromes present with very different craniofacial phenotypes which are reflective of SOX9/SOX10 specific defects during neural crest specialization. Work from this study will lead to the identification of novel SoxE transcriptional targets, determine when SoxE factors begin to promote neural crest specialization, and determine how specific patient variants for Campomelic dysplasia/Waardenburg syndrome cause disease phenotypes. Overall, this work is of high clinical significance and will provide evolutionary insights into the molecular origins of neural crest diversification.