394V Poster Online - Virtual Posters
Wednesday April 06, 4:00 PM - 7:00 PM

Authors:
Hadi Boukhatmi ^{1, 2, 5, 6}; Nourhene Ammar ^{1, 2}; Sarah Bray ^{5, 6}; Jennifer Zannet ^{3, 4}; François Payre ^{3, 4}

Affiliations:
1) Institut de Génétique et Développement de Rennes, CNRS, Rennes ; 2) Université de Rennes 1 ; 3) Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Intégrative (CBI), CNRS, Toulouse ; 4) Université Paul Sabatier ; 5) University of Cambridge ; 6) Department of Physiology, Development and Neuroscience.

Keywords:
k. regeneration; a. core promoters and general transcription factors

To compensate for damages and cell death, adult tissue homeostasis requires regeneration operated by long-lived stem cells. Skeletal muscles are regenerated by muscular stem cells called satellite cells (MuSC), which are quiescent and, upon injury, become activated and differentiate into myoblasts to repair muscles. A key question is how such cells are specified and then protected from differentiation for a prolonged developmental period. We discovered that MuSC maintenance involves persistent expression of the Zfh1/ZEB Transcription Factor (TF). We showed that sustained Zfh1 expression, in MuSC requires production of an alternate zfh1 RNA isoform, which is insensitive to microRNAs (miR8/miR200) degradation. Zfh1 protein is thus maintained in these cells, enabling them to escape differentiation and persist in the adult and contribute to muscle homeostasis. The key role of ZEB1 in the control of mammalian MuSCs maintenance has been recently reported, showing the broad relevance of Drosophila toward a better understanding of MuSC regulation.
While MuSC specification and differentiation starts to be well understood, little is known about the genetic control that underlies the early steps of their activation. Our results revealed that another conserved TF, OvoL/Shavenbaby (Svb), is expressed in adult MuSCs. Svb is the unique Drosophila member of the OvoL family of TFs, which are emerging as key regulators of epithelial tissues and stem cells. We found that the Svb TF binds in vivo to zfh1 cis-regulatory regions suggesting a direct regulation of zfh1 transcription by Svb. Interestingly, svb is rapidly turned off in new-born differentiating progenies that replenish the muscle fibre. Upon svb loss of function in adult MuSCs, we observed dramatic increase in the rate of myogenic progenitor production indicating that Svb controls the frequency of MuSC division rate. Building on these data, we concluded that Svb have a dual role in MuSCs: a) Maintaining stemness through zfh1, b) Acting as an early activating gene by regulating the rate of MuSC division.