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2009-10-17 - Colloque/Présentation - poster - Anglais - 1 page(s)

Charron Sébastien , Vanderplanck Céline, Belayew Alexandra , Coppée Frédérique , "WNT and FOXO signaling pathways in FSHD" in Protein modifications in development and diseases , Liège, Belgique, 2009

  • Codes CREF : Sciences biomédicales (DI3200), Biologie moléculaire (DI3111)
  • Unités de recherche UMONS : Biologie moléculaire (M122)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé)

Abstract(s) :

(Anglais) Facioscapulohumeral muscular dystrophy (FSHD) is a dominant disorder with a prevalence of 1 in 20,000 birth. It is characterized by muscle degeneration and atrophy progressing asymmetrically in an antero-posterior gradient, affecting first the face,followed by the scapulae and the foot dorsiflexors. At the age of 45, 20% of patients are wheelchair-dependent. Primary myoblasts derived from FSHD muscle biopsies are more sensitive to an induced oxidative stress than control myoblasts and present a differentiation defect. The genetic defect is linked to contractions of a 3.3-Kb repeated element named D4Z4 in the 4q35 subtelomeric region. In non affected individuals there are at least 11 copies of the D4Z4 unit while patients only have 1 to 10 copies left. The molecular mechanism of FSHD is complex and involves a change in chromatin structure that upregulates the expression of several proximal genes. Our group has identified the DUX4 gene within each D4Z4 element and the homologous DUX4c gene proximal to the repeat array. DUX4 is a transcription factor that targets a large set of genes in primary myoblasts, among which PITX1 expressing another transcription factor that is specifically induced in FSHD, and MYOD that is inhibited, leading to differentiation defects. Several targets of the WNT and FOXO intracellular signaling pathways are found among the hundreds of genes dysregulated in FSHD. We want to study their contribution to the FSHD phenotype and their link with DUX4/DUX4c/PITX1 expression. We first evaluated the WNT pathway status with a luciferase reporter vector. This vector contains TCF/LEF transcriptional response elements linked to a firefly luciferase reporter gene. TCF/LEF is directly activated by beta-catenin, the key element of an acitvated WNT pathway. Upon transfection of C2C12 mouse myoblasts with a DUX4 expression vector, we observed a 30-fold increase of luciferase activity as compared to controls. In a second experiment, we analyzed the expression of Atrogin 1 (MAFbx) and MuRF1, two E3 ubiquitin ligases specifically induced by FOXO during muscle atrophy. Their expression was increased both in FSHD myoblasts and in control myoblasts transfected with a DUX4 expression vector as compared to controls. In conclusion this study showed an activation of the WNT pathway in FSHD myoblasts and suggested a role for DUX4 in this process. In addition we showed that DUX4 could activate genes involved in muscle atrophy.