ESCRT-II/Vps25 constrains digit number by endosome-mediated selective modulation of FGF-SHH signaling

Karen Handschuh, Jennifer Feenstra, Matthew Koss, Elisabetta Ferretti, Maurizio Risolino, Rediet Zewdu, Michelle A Sahai, Jean-Denis Bénazet, Xiao P Peng, Michael J Depew, Laura Quintana, James Sharpe, Baolin Wang, Heather Alcorn, Roberta Rivi, Stephen Butcher, J Robert Manak, Thomas Vaccari, Harel Weinstein, Kathryn V AndersonElizabeth Lacy, Licia Selleri

Research output: Contribution to journalArticle

Abstract

Sorting and degradation of receptors and associated signaling molecules maintain homeostasis of conserved signaling pathways during cell specification and tissue development. Yet, whether machineries that sort signaling proteins act preferentially on different receptors and ligands in different contexts remains mysterious. Here, we show that Vacuolar protein sorting 25, Vps25, a component of ESCRT-II (Endosomal Sorting Complex Required for Transport II), directs preferential endosome-mediated modulation of FGF signaling in limbs. By ENU-induced mutagenesis, we isolated a polydactylous mouse line carrying a hypomorphic mutation of Vps25 (Vps25(ENU)). Unlike Vps25-null embryos we generated, Vps25(ENU/ENU) mutants survive until late gestation. Their limbs display FGF signaling enhancement and consequent hyperactivation of the FGF-SHH feedback loop causing polydactyly, whereas WNT and BMP signaling remain unperturbed. Notably, Vps25(ENU/ENU) Mouse Embryonic Fibroblasts exhibit aberrant FGFR trafficking and degradation; however, SHH signaling is unperturbed. These studies establish that the ESCRT-II machinery selectively limits FGF signaling in vertebrate skeletal patterning.

Original languageEnglish
Pages (from-to)674-87
Number of pages14
JournalCell Reports
Volume9
Issue number2
DOIs
Publication statusPublished - 23 Oct 2014

Keywords

  • Animals
  • Endosomal Sorting Complexes Required for Transport
  • Endosomes
  • Extremities
  • Feedback, Physiological
  • Fibroblast Growth Factors
  • Fibroblasts
  • Hedgehog Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Polydactyly
  • Signal Transduction
  • Vesicular Transport Proteins

Cite this

Handschuh, K., Feenstra, J., Koss, M., Ferretti, E., Risolino, M., Zewdu, R., Sahai, M. A., Bénazet, J-D., Peng, X. P., Depew, M. J., Quintana, L., Sharpe, J., Wang, B., Alcorn, H., Rivi, R., Butcher, S., Manak, J. R., Vaccari, T., Weinstein, H., ... Selleri, L. (2014). ESCRT-II/Vps25 constrains digit number by endosome-mediated selective modulation of FGF-SHH signaling. Cell Reports, 9(2), 674-87. https://doi.org/10.1016/j.celrep.2014.09.019