Gliogenesis and maintenance of glial cell types are critical to development and function of the nervous system. Sox10 is a developmental transcription factor that is essential for development of multiple glial lineages including oligodendrocytes in the central nervous system as well as neural crest-derived Schwann cells, satellite glia and enteric nervous system neurons and glia in the periphery. Investigating Sox10 function in these distinct populations has been difficult because simple gene knockouts cause complete loss of gene expression in early neural crest progenitors resulting in embryonic lethality. Efforts to temporally induce loss of Sox10 have been hampered by kinetics of mRNA and protein decay. In the context of the R03 mechanism we propose generation of a COnditional INducible (""""""""COIN"""""""") dominant negative allele of Sox10 in mice as a novel tool for analysis of gene function.
Specific Aim 1 will generate mice bearing a COIN cassette in the Sox10 locus that upon Cre action results in expression of a fluorescently tagged dominant negative Sox10 isoform.
Specific Aim 2 will define the effects of the Sox10COIN allele on oligodendrocyte and enteric neural crest-derived lineages before and after COIN inversion. The ability to conditionally disrupt Sox10 expression and function in distinct populations will significantly impact the field by opening avenues for analysis of developmental mechanisms that are relevant for directed differentiation of progenitors cells to treat central and peripheral neuropathies.
The goal of this proposal is to develop a novel mouse mutant that can be used to investigate development and model deficits of the peripheral nervous system. Understanding how the nervous system develops and maintains itself has important clinical implications since failure to do so can result in a number of peripheral neuropathies ranging from loss of muscle control to gastrointestinal motility disorders, inability to sense pain or change in temperature and neuropathic pain. Using such mouse models helps direct differentiation of stem cell populations for treatment of congenital disorders or restoration of nervous system damage due to disease or trauma.
