title: A truncated Wnt7a retains full biological activity in skeletal muscle.
abstract: Wnt signaling has essential roles during embryonic development and tissue homoeostasis. Wnt proteins are post-translationally modified and the attachment of a palmitate moiety at two conserved residues is believed to be a prerequisite for the secretion and function of Wnt proteins. Here we demonstrate that a mammalian Wnt protein can be fully functional without palmitoylation. We generate a truncated Wnt7a variant, consisting of the C-terminal 137 amino acids lacking the conserved palmitoylation sites and show that it retains full biological activity in skeletal muscle. This includes binding to and signaling through its receptor Fzd7 to stimulate symmetric expansion of satellite stem cells by activating the planar-cell polarity pathway and inducing myofibre hypertrophy by signaling through the AKT/mTOR pathway. Furthermore, this truncated Wnt7a shows enhanced secretion and dispersion compared with the full-length protein. Together, these findings open important new avenues for the development of Wnt7a as a treatment for muscle-wasting diseases and have broad implications for the therapeutic use of Wnts as biologics.
authors.affiliation: 1] Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H8L6 [2] Leibniz Institute for Age Research, Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07445 Jena, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: von Maltzahn
authors.forename: Radoslav
authors.initials: R
authors.lastname: Zinoviev
authors.forename: Natasha C
authors.initials: NC
authors.lastname: Chang
authors.forename: C Florian
authors.initials: CF
authors.lastname: Bentzinger
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rudnicki
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D005260:Female; D051157:Frizzled Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D051153:Wnt Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D051157:Frizzled Receptors; C492041:Fzd7 protein, mouse; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; C490508:Wnt7a protein, mouse