Regulation of Skeletal Muscle Development And Differentiation by Ski

 
 
 
 

Regulation of Skeletal Muscle Development And Differentiation by Ski

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Title: Regulation of Skeletal Muscle Development And Differentiation by Ski
Author: Zhang, Hong
Description: Ski is the most studied member of a family of proteins all sharing a conserved Dachshund homology domain. It has been implicated in oncogenic transformation, myogenic conversion of avian embryo fibroblasts and also many aspects of vertebrate development, especially myogenesis. Ski-/- mice exhibit severe defects in skeletal muscle and die at birth, yet little is know about either the underlying mechanisms or the role of Ski in adult muscle regeneration. In these studies, I used Ski knockout mice and C2C12 myoblast cultures to address these issues, respectively. Detailed analysis of Ski-/- embryos revealed dramatically reduced hypaxial muscles but less affected epaxial muscles. The reduced number of myogenic regulatory factor positive cells in Ski-/- mice suggested an insufficient myogenic cell pool to support muscle formation. However, both the dermomyotomal hypaxial progenitors and myotomal epaxial progenitors formed and committed to myogenic fate appropriately. The hypaxial muscle defect in Ski-/- mice was not caused by abnormal proliferation, terminal differentiation or apoptosis of the myogenic cells either, but due to impaired migration of embryonic hypaxial progenitors. Surprisingly, the normal distribution of fetal/postnatal myogenic progenitors in Ski-/- mice suggested different effects of Ski on the behaviors of embryonic and fetal/postnatal myogenic progenitors. In addition, although not affecting the terminal differentiation of embryonic myogenic cells, Ski was necessary for that of adult satellite-cell derived C2C12 myoblasts as evidenced by impaired myotube formation and reduced induction of genes essential for myogenic differentiation in the absence of Ski. This function was mainly mediated by Ski’s ability to form a complex with Six1 and Eya3 and activate Myog transcription through a MEF3 site. It is important in the future to further study mechanisms underlying the contrasting effects of Ski on embryonic, fetal and adult muscle development, to investigate how the association of Ski with Six1/Eya3 is triggered upon differentiation and to identify the transcriptional machinery mediates Ski’s action. The data presented here not only add a new aspect to the understanding of myogenic progenitor migration and hypaxial muscle development but also provide a starting point to achieve the regulation of muscle formation and regeneration through the action of Ski.
Permanent Link: http://rave.ohiolink.edu/etdc/view?acc_num=case1226938149
http://hdl.handle.net/2374.OX/103975
Date: 2009

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