Somatic stem cell populations reside in adult tissues and participate in the maintenance and regeneration of adult tissues. The signaling networks that govern the somatic stem cell populations are ill defined. We have previously defined the forkhead/winged helix transcription factor, Foxk1, as the first molecular marker for the muscle stem cell population that resides in adult skeletal muscle. Using a gene disruption strategy, mice lacking Foxk1 have impaired muscle regeneration, decreased numbers of muscle stem cells that have perturbed cell cycle kinetics and an induction of the cyclin dependent kinase inhibitor, p21. We provide new preliminary data supporting a novel pathway whereby Foxk1 contributes to a repression complex that represses p21 resulting in the activation and proliferation of the muscle stem cell population. These preliminary data provide a platform for the studies, outlined in this revised grant application. The overall hypothesis of this proposal is that lineage specific transcriptional regulators interact and modulate the myogenic stem cell population to promote skeletal muscle regeneration. To address this hypothesis, we will pursue the following three specific aims:
Specific Aim #1 : To define the transcriptional regulation of the cyclin dependent kinase inhibitor, p21CIP in the muscle stem cell population.
Specific Aim #2 : To define the transcriptional role of Foxk1 as a critical regulator of the muscle stem cell population.
Specific Aim #3 : To define the functional role of Foxk1 overexpression in adult skeletal muscle. These studies will enhance our understanding of the transcriptional regulation of the myogenic stem cell population and the mechanisms, in part, that govern muscle regeneration following an injury or disease. Furthermore, the results of these studies will serve as a platform for therapeutic strategies directed towards the treatment of acquired myopathic diseases.

Public Health Relevance

Congenital and acquired myopathies are common and deadly. The capacity of adult tissues to regenerate in response to disease or injury is due to resident stem cell populations. The regulatory mechanisms that govern muscle stem cells are unknown. This proposal will decipher the molecular pathways that govern muscle stem cells and may ultimately lead to novel therapies directed towards an enhanced regenerative response in patients with myopathic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055906-04
Application #
8230787
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Boyce, Amanda T
Project Start
2009-04-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$315,723
Indirect Cost
$106,635
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Gong, Wuming; Gohla, Rachel M; Bowlin, Kathy M et al. (2015) Kelch Repeat and BTB Domain Containing Protein 5 (Kbtbd5) Regulates Skeletal Muscle Myogenesis through the E2F1-DP1 Complex. J Biol Chem 290:15350-61
Bowlin, Kathy M; Embree, Laurence J; Garry, Mary G et al. (2013) Kbtbd5 is regulated by MyoD and restricted to the myogenic lineage. Differentiation 86:184-91
Singh, Bhairab N; Doyle, Michelle J; Weaver, Cyprian V et al. (2012) Hedgehog and Wnt coordinate signaling in myogenic progenitors and regulate limb regeneration. Dev Biol 371:23-34
Shi, Xiaozhong; Garry, Daniel J (2012) Sin3 interacts with Foxk1 and regulates myogenic progenitors. Mol Cell Biochem 366:251-8
Shi, Xiaozhong; Seldin, David C; Garry, Daniel J (2012) Foxk1 recruits the Sds3 complex and represses gene expression in myogenic progenitors. Biochem J 446:349-57
Shi, Xiaozhong; Wallis, Alicia M; Gerard, Robert D et al. (2012) Foxk1 promotes cell proliferation and represses myogenic differentiation by regulating Foxo4 and Mef2. J Cell Sci 125:5329-37
Caprioli, Arianna; Koyano-Nakagawa, Naoko; Iacovino, Michelina et al. (2011) Nkx2-5 represses Gata1 gene expression and modulates the cellular fate of cardiac progenitors during embryogenesis. Circulation 123:1633-41
Rasmussen, Tara L; Raveendran, Ganesh; Zhang, Jianyi et al. (2011) Getting to the heart of myocardial stem cells and cell therapy. Circulation 123:1771-9
Alexander, Matthew S; Shi, Xiaozhong; Voelker, Kevin A et al. (2010) Foxj3 transcriptionally activates Mef2c and regulates adult skeletal muscle fiber type identity. Dev Biol 337:396-404
Shi, Xiaozhong; Garry, Daniel J (2010) Myogenic regulatory factors transactivate the Tceal7 gene and modulate muscle differentiation. Biochem J 428:213-21

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