title: Coordinated action of Axin1 and Axin2 suppresses β-catenin to regulate muscle stem cell function.
abstract: The resident stem cells of skeletal muscle are satellite cells, which are regulated by both canonical and non-canonical Wnt pathways. Canonical Wnt signalling promotes differentiation, and is controlled at many levels, including via Axin1 and Axin2-mediated β-catenin degradation. Axin1 and Axin2 are thought equivalent suppressors of canonical Wnt signalling, although Axin2 is also a Wnt target gene. We show that Axin1 expression was higher in proliferating satellite cells, while Axin2 was up-regulated during differentiation. siRNA-mediated Axin1 knockdown changed cell morphology, suppressed proliferation and promoted myogenic differentiation. Simultaneous knockdown of both Axin1 and β-catenin rescued proliferation and partially, premature differentiation. Surprisingly, retroviral-mediated overexpression of Axin2 was unable to compensate for knockdown of Axin1 in satellite cells, indicating that Axin1 and Axin2 are not fully redundant. Isolated satellite cells from Axin2-null mice also had no major phenotype. However, siRNA-mediated knockdown of Axin1 in Axin2-null cells strongly inhibited proliferation, while inducing differentiation, clear nuclear localisation of β-catenin, up-regulation of canonical Wnt target genes (Axin2, Lef1, Tcf4, Pitx2c and Lgr5) and activation of a TCF reporter construct. Again, concomitant knockdown of Axin1 and β-catenin in Axin2-null satellite cells rescued morphology and proliferation, but only partially prevented precocious differentiation. Thus, Axin1 and Axin2 do not have equivalent functions in satellite cells, but are both involved in repression of Wnt/β-catenin signalling to maintain proliferation and contribute to controlling timely myogenic differentiation.
authors: King's College London, Randall Division of Cell & Molecular Biophysics, New Hunt's House, Guy's Campus, United Kingdom. Electronic address: nicolas.figeac@kcl.ac.uk.
authors: Nicolas
authors: N
authors: Figeac
authors: King's College London, Randall Division of Cell & Molecular Biophysics, New Hunt's House, Guy's Campus, United Kingdom. Electronic address: peter.zammit@kcl.ac.uk.
authors: Peter S
authors: PS
authors: Zammit
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D048430:Cell Shape; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D034622:RNA Interference; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D060466:Axin Protein; C555452:Axin1 protein, mouse; C111729:Axin2 protein, mouse; C495267:CTNNB1 protein, mouse; D051176:beta Catenin
keywords: Axin1; Axin2; Satellite cell; Skeletal muscle; Stem cell; β-catenin