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 Anderson; Elizabeth Lacy; Licia Selleri

doi:10.1016/j.celrep.2014.09.019

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

Journal article

Open access

Peer reviewed

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, …

Cell reports (Cambridge), Vol.9(2), pp.674-687

10/23/2014

DOI: 10.1016/j.celrep.2014.09.019

PMCID: PMC4223648

PMID: 25373905

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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.

Animals

Endosomal Sorting Complexes Required for Transport - genetics

Endosomal Sorting Complexes Required for Transport - metabolism

Endosomes - metabolism

Extremities - growth & development

Feedback, Physiological

Fibroblast Growth Factors - metabolism

Fibroblasts - metabolism

Hedgehog Proteins - metabolism

Mice

Mice, Inbred C57BL

Mutation

Polydactyly - genetics

Polydactyly - metabolism

Signal Transduction

Vesicular Transport Proteins - genetics

Vesicular Transport Proteins - metabolism

Details

Title: Subtitle: ESCRT-II/Vps25 constrains digit number by endosome-mediated selective modulation of FGF-SHH signaling
Creators: Karen Handschuh - Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA
Jennifer Feenstra - Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA
Matthew Koss - Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA
Elisabetta Ferretti - Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA
Maurizio Risolino - Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA
Rediet Zewdu - Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA
Michelle A Sahai - Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA
Jean-Denis Bénazet - Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA
Xiao P Peng - Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA
Michael J Depew - Department 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
Laura Quintana - Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA; Centre for Genomic Regulation (CRG), 08003 Barcelona, Spain
James Sharpe - Centre 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
Baolin Wang - Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA
Heather Alcorn - Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA
Roberta Rivi - Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA
Stephen Butcher - Departments of Biology and Pediatrics, University of Iowa, Iowa City, IA 52242, USA
J Robert Manak - Departments of Biology and Pediatrics, University of Iowa, Iowa City, IA 52242, USA
Thomas Vaccari - IFOM-FIRC Institute of Molecular Oncology, 20139 Milan, Italy
Harel Weinstein - Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA
Kathryn V Anderson - Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA
Elizabeth Lacy - Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA
Licia Selleri - Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: lis2008@med.cornell.edu
Resource Type: Journal article
Publication Details: Cell reports (Cambridge), Vol.9(2), pp.674-687
DOI: 10.1016/j.celrep.2014.09.019
PMID: 25373905
PMCID: PMC4223648
NLM abbreviation: Cell Rep
ISSN: 2211-1247
eISSN: 2211-1247
Grant note: U01 HG004080 / NHGRI NIH HHS R21 DE018031 / NIDCR NIH HHS 2R01HD043997 / NICHD NIH HHS R01 HD043997 / NICHD NIH HHS U01HG004080 / NHGRI NIH HHS P30 CA008748 / NCI NIH HHS T32 GM007739 / NIGMS NIH HHS R21DE018031 / NIDCR NIH HHS R21DE018031-02S1 / NIDCR NIH HHS U42RR024244 / NCRR NIH HHS R37 HD035455 / NICHD NIH HHS U01 HG004085 / NHGRI NIH HHS U42 RR024244 / NCRR NIH HHS U01HG004085 / NHGRI NIH HHS
Language: English
Date published: 10/23/2014
Academic Unit: Stead Family Department of Pediatrics; Biology; Craniofacial Anomalies Research Center
Record Identifier: 9984217541302771

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