Institute of Development, Aging and Cancer, Tohoku University

Research

Seminars and Symposia

IDAC Seminar, 11 March 2011

Secretariat, Alumni Association, IDAC
Date Friday, 11 March 2011,14:00~
Room Seminar-shitsu 1,2, IDAC Research building.
Title Regulation of muscle stem cell fate by Pax genes
Speaker Margaret Buckingham
Affiliation Pasteur Institute
Person-in-charge Toshihiko Ogura Dept.Developmental Neurobiology
Contact: Yusuke Watanabe(ex 8596)
Abstract Pax3 and Pax7 mark myogenic progenitor cells and play a critical role in regulating their entry into the myogenic programme. We had shown that in the Pax3/7-/- double mutant the myogenic determination genes, Myf5 and MyoD are not activated, leading to a major deficit in skeletal muscle. Pax3 directly activates Myf5, thus promoting a myogenic cell fate. However, it is essential to maintain a balance between differentiation and renewal of the progenitor cell population. We have shown that this can be achieved by Pax3 modulation of FGF signaling via Sprouty1 and Fgfr4 which is a direct Pax3 target. Other Pax3 targets will be discussed, including Dmrt2 and Foxc2, both expressed in the dermomyotome, the part of the somite from which skeletal muscle cells derive. Foxc2 is negatively regulated by Pax3 and in turn feeds back negatively on Pax3/7 expression. This negative feedback loop is implicated in cell fate decisions of the multipotent Pax3/7 positive stem cells of the dermomyotome. These cells can form derm, brown fat, endothelial and smooth muscle cells of blood vessels as well as skeletal muscle. Taking the latter tissues as an example, we show genetically that up-regulation of Foxc2 promotes endothelial and smooth muscle cell fates whereas Pax3/7 promote myogenesis. This is also demonstrated by manipulation of these factors in somite explants. Signaling from adjacent tissues, such as the dorsal ectoderm, affects the equilibrium between Pax3/7:Foxc2 and the choice of cell fate of the multipotent cells expressing these genes in the dermomyotome. The skeletal muscle cell fate is also dependent on Pax3 in mesodermal stem cells such as mesoangioblasts. In post-natal skeletal muscle, growth and regeneration are assured by satellite cells, derived from the Pax3/7 expressing cells of the embryonic somites. However it has emerged recently that Pax3/7 are no longer essential for the function of these cells in adult muscle where many satellite cells already transcribe Myf5. These cells do not accumulate Myf5 protein and it is only when activated, after injury, that this myogenic determination factor is present, with consequent myogenesis and formation of new muscle fibres. We propose that microRNA 31 contributes to the down-regulation of Myf5 and prevention of premature myogenesis in the quiescent satellite cells of adult muscle.
参考文献
Nature 435:948-53 (2005), Science 309:2064-7 (2005), JCB 172:91-102 (2006), Genes Dev 20:2450-64 (2006), Genes Dev 22:1828-37 (2008),
PNAS 106:13383-7 (2009), Dev Cell 17:892-9 (2009) etc