My career goal is to be an independent investigator researching the function of transcriptional regulation of stem cells towards improving therapies for regenerative medicine. In this project, I will use mouse models to study the regulation of a stem cell population called muscle satellite cells (MuSCs). The regenerative function of MuSCs are controlled by gene regulatory networks (often transcriptional factors) that govern cell fate choice among self-renewal, quiescence and/or differentiation. Our lab has recently employed single-cell RNA- sequencing to profile gene expression of various cell populations during muscle regeneration. This assay led to the identification of the transcription factor Sox11 as a candidate marker for MuSCs and a potential regulator of MuSC differentiation. Studies suggest that Sox11 may regulate the expression of genes involved in the WNT/ ?-catenin-signaling pathway, which has been shown to induce myogenesis during development and promote differentiation of adult MuSCs in response to injury. To understand the genetic requirement and mechanism of Sox11 in MuSCs, the proposal will address the following aims: (1) Determine the necessity for Sox11 in skeletal muscle development and in response to injury. We will use conditional and inducible mouse models to specifically knock-out Sox11 in muscle progenitors and in the adult MuSC pool. These experiments will allow us to evaluate our hypothesis that Sox11 is essential for the differentiation of MuSCs in vivo. (2) Assess the role Sox11 plays in WNT-signaling and determine if WNT activation can restore differentiation defects in Sox11-KO myoblasts.
This aim will evaluate our hypothesis that Sox11 regulates WNT-signaling pathway genes to secure myoblast differentiation. While the essential function of Sox11 has been described in other tissues, its role in myogenesis is unknown. This research proposal has the potential to identify Sox11 as novel regulator of MuSC function via its transcriptional regulation of WNT-pathway components. This proposal will undoubtedly provide excellent training in the field of gene regulation as it pertains to muscle stem cell function.
Skeletal muscle satellite cells (MuSCs) are an adult stem cell population required for skeletal muscle repair however, MuSC function declines with age and is dysregulated in neuromuscular disorders. Transcription factors are critical for MuSC function and lend insight into gene regulatory networks that can be targeted for therapies. We have identified Sox11 as a candidate regulator of MuSC differentiation and will investigate the genetic and molecular requirement for Sox11 using both in vivo and in vitro approaches.
