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Cell Rep. 2014 Oct 23;9(2):674-87. doi: 10.1016/j.celrep.2014.09.019. Epub 2014 Oct 16.

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

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  • 1Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
  • 2Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
  • 3Department of Craniofacial Development, King's College London, Guy's Hospital, London Bridge, London SE1 9RT, UK; Department of Othopaedic Surgery, UCSF, San Francisco, CA 94110, USA.
  • 4Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA; Centre for Genomic Regulation (CRG), 08003 Barcelona, Spain.
  • 5Centre for Genomic Regulation (CRG), 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain; Institucio Catalana de Recerca i Estudis Avancats (ICREA), 08010 Barcelona, Spain.
  • 6Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
  • 7Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA.
  • 8Departments of Biology and Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
  • 9IFOM-FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
  • 10Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: lis2008@med.cornell.edu.

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.

PMID:
25373905
PMCID:
PMC4223648
DOI:
10.1016/j.celrep.2014.09.019
[PubMed - indexed for MEDLINE]
Free PMC Article
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