1. Hedgehog-Gli activation during rhabdomyosarcoma genesis in postnatal mice
- Author
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Rajurkar, Mihir, Huang, He, Cotton, Jennifer L., Brooks, Julie K., Sicklick, Jason, McMahon, Andrew P., and Mao, Junhao
- Subjects
Mice, Knockout ,Mice, 129 Strain ,Satellite Cells, Skeletal Muscle ,Reverse Transcriptase Polymerase Chain Reaction ,Immunoblotting ,Kruppel-Like Transcription Factors ,PAX7 Transcription Factor ,Nerve Tissue Proteins ,Zinc Finger Protein Gli2 ,Smoothened Receptor ,Zinc Finger Protein GLI1 ,Article ,Receptors, G-Protein-Coupled ,SOXC Transcription Factors ,Gene Expression Regulation, Neoplastic ,Zinc Finger Protein Gli3 ,Rhabdomyosarcoma ,Tumor Cells, Cultured ,Animals ,Humans ,Cell Lineage ,Hedgehog Proteins ,RNA Interference ,Cells, Cultured - Abstract
Dysregulation of the Hedgehog (Hh)-Gli signaling pathway is implicated in a variety of human cancers, including basal cell carcinoma (BCC), medulloblastoma (MB), and embryonal rhabdhomyosarcoma (eRMS), three principle tumors associated with human Gorlin syndrome. However, the cellular origins of these tumors, including eRMS, remain poorly understood. In this study, we explore the cell populations that give rise to Hh-related tumors by specifically activating Smoothened (Smo) in both Hh-producing and -responsive cell lineages in postnatal mice. Interestingly, we find that unlike BCC and MB, eRMS originates from the stem/progenitor populations that do not normally receive active Hh signaling. Furthermore, we find that the myogenic lineage in postnatal mice is largely Hh quiescent and that Pax7-expressing muscle satellite cells are not able to give rise to eRMS upon Smo or Gli1/2 over-activation in vivo, suggesting that Hh-induced skeletal muscle eRMS arises from Hh/Gli quiescent non-myogenic cells. In addition, using the Gli1 null allele and a Gli3 repressor allele, we demonstrate the genetic requirement for Gli proteins in Hh-induced eRMS formation and provide molecular evidence for the involvement of SoxC factors in Hh-dependent eRMS cell survival and differentiation.
- Published
- 2013