Date of Award

Spring 1-1-2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Mark Winey

Second Advisor

Bradley Olwin

Third Advisor

David L. Allen

Fourth Advisor

Leslie A. Leinwand

Fifth Advisor

Rui Yi

Abstract

Skeletal muscle is maintained and repaired by satellite cells. Satellite cells are quiescent in uninjured muscle but activate, proliferate and repair the muscle after injury. The quiescent satellite cell population is renewed during the injury repair, but how and when this happens is unclear. Recently, several subpopulations of satellite cells have been described with an enhanced capacity for self-renewal raising the possibility that there is a subset of satellite cells dedicated to maintaining the quiescent satellite cell population. I find that all satellite cells activate in response to injury and, after the first division, quiescent satellite cells reappear. I show that these quiescent cells are generated by a subpopulation of satellite stem cells that divide asymmetrically in response to muscle injury. During this division, Jam2 establishes asymmetry by recruiting the Par complex to sites of cell-cell or cell-fiber junctions and only one daughter cell receives the Jam2/Par complex. The Par complex associates with Tiam1 and promotes the activation of p38α/β MAPK through a novel signaling pathway, promoting proliferation and commitment to myogenesis in only one daughter. The Jam2 expressed in this daughter cell promotes quiescence in the adjacent daughter cell through the Jam2 extracellular domain. This asymmetric division results in an active myoblast and a quiescent cell that retains the satellite stem cell identity. Thus, the asymmetric activation of p38ɑ/β MAPK by the Par complex and the lateral regulation of quiescence by Jam2 ensures the self-renewal of the satellite stem cell population. The timing of this asymmetric division illustrates a novel link between the initial response to muscle injury and satellite cell self-renewal. This is potentially a mechanism for satellite cells to gage the severity of the muscle injury and organize the satellite cell response accordingly.

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