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Adult satellite cells and embryonic muscle progenitors have distinct genetic requirements

Abstract

Myogenic potential, survival and expansion of mammalian muscle progenitors depend on the myogenic determinants Pax3 and Pax7 embryonically1, and Pax7 alone perinatally2,3,4,5. Several in vitro studies support the critical role of Pax7 in these functions of adult muscle stem cells5,6,7,8 (satellite cells), but a formal demonstration has been lacking in vivo. Here we show, through the application of inducible Cre/loxP lineage tracing9 and conditional gene inactivation to the tibialis anterior muscle regeneration paradigm, that, unexpectedly, when Pax7 is inactivated in adult mice, mutant satellite cells are not compromised in muscle regeneration, they can proliferate and reoccupy the sublaminal satellite niche, and they are able to support further regenerative processes. Dual adult inactivation of Pax3 and Pax7 also results in normal muscle regeneration. Multiple time points of gene inactivation reveal that Pax7 is only required up to the juvenile period when progenitor cells make the transition into quiescence. Furthermore, we demonstrate a cell-intrinsic difference between neonatal progenitor and adult satellite cells in their Pax7-dependency. Our finding of an age-dependent change in the genetic requirement for muscle stem cells cautions against inferring adult stem-cell biology from embryonic studies, and has direct implications for the use of stem cells from hosts of different ages in transplantation-based therapy.

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Figure 1: Adult-specific Pax7 mutant cells regenerate muscle efficiently.
Figure 2: Adult-specific Pax7 mutant cells are functional satellite cells.
Figure 3: Pax3 and Pax7 are dispensable for adult muscle regeneration.
Figure 4: Age-dependent intrinsic change of Pax7 requirement.

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Acknowledgements

We thank E. Dikovskaia and E. Siple for technical assistance and Y. Zheng, A. Spradling, S.-J. Lee and J. J. Weyers for comments on the manuscript. D. Barry and K. R. Wagner taught us muscle injury techniques and sample preparation. The Carnegie Institution, NIH and Riley Children’s Foundation provided funding for this work.

Author Contributions C.L. and C.-M.F. designed and conducted the research. S.J.C. provided the Pax3f allele and invaluable information. All three authors contributed to manuscript writing.

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Correspondence to Christoph Lepper or Chen-Ming Fan.

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Lepper, C., Conway, S. & Fan, CM. Adult satellite cells and embryonic muscle progenitors have distinct genetic requirements. Nature 460, 627–631 (2009). https://doi.org/10.1038/nature08209

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