Pax3 is a key regulator of developmental and postnatal myogenesis. However, the specific role of Pax3 in the regulation of adult muscle stem cell (satellite cell (SC)) function remains poorly understood. In the melanocyte lineages, Pax3 is known to be a nodal regulator, simultaneously activating a determination program, thereby maintaining the lineage identity of the progenitor, while preventing terminal differentiation. Based on preliminary studies, we hypothesize that Pax3 plays a similar role in the myogenic lineage of SCs. For such a critical regulator, control of expression is essential such that the transition between committed progenitors to more differentiated progeny is orchestrated in a precise temporal fashion. As such, Pax3 levels are controlled post-transcriptionally by regulation of protein stability as we have shown previously. In more recent studies, we found that Pax3 is also regulated by a microRNA, miR-206, to control transcript levels during SC activation. Even more intriguingly, we found that different subsets of SCs choose different polyadenylation signals when transcribing Pax3, resulting in SCs with Pax3 transcripts that contain miR-206 target sites and other SCs with Pax3 transcripts that contain no miR-206 target sites. The latter are therefore resistant to regulation by miR-206 and express high levels of Pax3 in the quiescent state. We will build upon these observations and preliminary data to explore in more detail the function and regulation of Pax3 during SC activation. As such, the Specific Aims of this proposal are (1) to explore the role of Pax3 as a nodal regulator of adult SCs and their progeny; (2) to examine the regulation of Pax3 levels by miR-206; and (3) to study the role of alternate polyadenylation signal selection in determining the ability of miR-206 to regulate Pax3 levels. Together, these studies will greatly expand our understanding of the role of Pax3 in postnatal myogenesis.
The ability of tissues within the body to repair themselves after an injury or in response to degenerative disease processes is due to the presence of stem cells in those various tissues. In skeletal muscle, stem cells remain in a 'quiescent state', in reserve to be called upon if any injury occurs. A major focus of our research is to understand the molecules that signal to those quiescent stem cells to begin the process of tissue repair, and the signals within those cells that control when they begin to divide, how many times they divide, and how to make mature muscle and not some other tissue. One of the key molecules within muscle stem cells that controls many of these processes is Pax3. In the studies of this proposal, we will study how the level of Pax3 is regulated and which cellular functions are controlled by Pax3 when it is produced. Overall, these studies will lead to a better understanding of the regulation of muscle stem cell function and to potential ways to improve muscle repair in the setting of degenerative diseases like muscular dystrophies.
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