Coordinated action of Axin1 and Axin2 suppresses β-catenin to regulate muscle stem cell function

TY - JOUR

T1 - Coordinated action of Axin1 and Axin2 suppresses β-catenin to regulate muscle stem cell function

AU - Figeac, Nicolas

AU - Zammit, Peter S.

PY - 2015/8/1

Y1 - 2015/8/1

N2 - 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.

AB - 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.

KW - Axin1

KW - Axin2

KW - Satellite cell

KW - Skeletal muscle

KW - Stem cell

KW - β-catenin

UR - http://www.scopus.com/inward/record.url?scp=84930178390&partnerID=8YFLogxK

U2 - 10.1016/j.cellsig.2015.03.025

DO - 10.1016/j.cellsig.2015.03.025

M3 - Article

AN - SCOPUS:84930178390

SN - 0898-6568

VL - 27

SP - 1652

EP - 1665

JO - Cellular Signalling

JF - Cellular Signalling

IS - 8

ER -