Date of Award

Spring 2010

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Bradley B. Olwin

Second Advisor

Corrella Detweiler

Third Advisor

Leslie A. Leinwand

Abstract

In animals, tissue maintenance, plasticity and repair rely on adult stem cells which have been identified in nearly all tissues. Many adult stem cells are typically quiescent and only activate when required for maintenance and repair of adult tissues. Within hours of activation skeletal muscle stem cells called satellite cells begin to express MyoD, a muscle-specific transcription factor that functions as a master regulator, committing satellite cells to myogenesis. The earliest detectable event in satellite cells following muscle injury is phosphorylation of p38α/β MAPKs, which is required for MyoD induction and cell-cycle entry. Loss of Syndecan-4, a component of the satellite cell niche disrupts p38α/β MAPK activation and severely delays MyoD induction. We performed a microarray gene chip experiment to identify genes expressed during satellite cell activation. We identified differentially expressed genes by subtracting genes changing in Sdc4-/- satellite cells from those changing in WT satellite cells following 12h of muscle injury. Unexpectedly, we observed that 70% of RNA-binding proteins (RNA-BPs) decreased in activated satellite cells. Expression levels of the Tristetraprolin (TTP) family of RNA-BPs declined dramatically as satellite cells activated. The TTP family is known to direct mRNA decay and we identified the 3‘UTR of MyoD as a direct TTP target. Furthermore, p38α/β MAPK signaling inhibits TTP-mediated mRNA decay in satellite cells. HuR, an RNA-BP that is induced during satellite cell activation is known to stabilize MyoD mRNA. The coordinate inhibition of TTP and induction of HuR may together function as a feed-forward loop to commit satellite cells to myogenesis by rapid induction of MyoD. A similar feed-forward circuit could operate in other stem cell systems, implicating that post-transcriptional regulation of mRNA could play a major role in regulating adult stem cells to maintain and repair adult tissues.

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Molecular, Cellular, and Developmental Biology

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