ESCRT-II/Vps25 Constrains Digit Number by Endosome-Mediated Selective Modulation of FGF-SHH Signaling
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 cont...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2014-10-01
|
| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124714007876 |
| _version_ | 1818234102518644736 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Karen Handschuh |
| collection | DOAJ |
| description | 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 (Vps25ENU). Unlike Vps25-null embryos we generated, Vps25ENU/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, Vps25ENU/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. |
| first_indexed | 2024-12-12T11:32:44Z |
| format | Article |
| id | doaj.art-fac2dc6a120c4b5a81b814c1c6b66887 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-12T11:32:44Z |
| publishDate | 2014-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-fac2dc6a120c4b5a81b814c1c6b668872022-12-22T00:25:45ZengElsevierCell Reports2211-12472014-10-019267468710.1016/j.celrep.2014.09.019ESCRT-II/Vps25 Constrains Digit Number by Endosome-Mediated Selective Modulation of FGF-SHH SignalingKaren Handschuh0Jennifer Feenstra1Matthew Koss2Elisabetta Ferretti3Maurizio Risolino4Rediet Zewdu5Michelle A. Sahai6Jean-Denis Bénazet7Xiao P. Peng8Michael J. Depew9Laura Quintana10James Sharpe11Baolin Wang12Heather Alcorn13Roberta Rivi14Stephen Butcher15J. Robert Manak16Thomas Vaccari17Harel Weinstein18Kathryn V. Anderson19Elizabeth Lacy20Licia Selleri21Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USADepartment of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USADepartment of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USADepartment of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USADepartment of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USADepartment of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USADepartment of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USADepartment of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USADepartment of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USADepartment of Craniofacial Development, King’s College London, Guy’s Hospital, London Bridge, London SE1 9RT, UKDepartment of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USACentre for Genomic Regulation (CRG), 08003 Barcelona, SpainDepartment of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USADevelopmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USADevelopmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USADepartments of Biology and Pediatrics, University of Iowa, Iowa City, IA 52242, USADepartments of Biology and Pediatrics, University of Iowa, Iowa City, IA 52242, USAIFOM-FIRC Institute of Molecular Oncology, 20139 Milan, ItalyDepartment of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USADevelopmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USADevelopmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USADepartment of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USASorting 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 (Vps25ENU). Unlike Vps25-null embryos we generated, Vps25ENU/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, Vps25ENU/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.http://www.sciencedirect.com/science/article/pii/S2211124714007876 |
| spellingShingle | 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 ESCRT-II/Vps25 Constrains Digit Number by Endosome-Mediated Selective Modulation of FGF-SHH Signaling Cell Reports |
| title | ESCRT-II/Vps25 Constrains Digit Number by Endosome-Mediated Selective Modulation of FGF-SHH Signaling |
| title_full | ESCRT-II/Vps25 Constrains Digit Number by Endosome-Mediated Selective Modulation of FGF-SHH Signaling |
| title_fullStr | ESCRT-II/Vps25 Constrains Digit Number by Endosome-Mediated Selective Modulation of FGF-SHH Signaling |
| title_full_unstemmed | ESCRT-II/Vps25 Constrains Digit Number by Endosome-Mediated Selective Modulation of FGF-SHH Signaling |
| title_short | ESCRT-II/Vps25 Constrains Digit Number by Endosome-Mediated Selective Modulation of FGF-SHH Signaling |
| title_sort | escrt ii vps25 constrains digit number by endosome mediated selective modulation of fgf shh signaling |
| url | http://www.sciencedirect.com/science/article/pii/S2211124714007876 |
| work_keys_str_mv | AT karenhandschuh escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT jenniferfeenstra escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT matthewkoss escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT elisabettaferretti escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT mauriziorisolino escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT redietzewdu escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT michelleasahai escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT jeandenisbenazet escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT xiaoppeng escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT michaeljdepew escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT lauraquintana escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT jamessharpe escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT baolinwang escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT heatheralcorn escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT robertarivi escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT stephenbutcher escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT jrobertmanak escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT thomasvaccari escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT harelweinstein escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT kathrynvanderson escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT elizabethlacy escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling AT liciaselleri escrtiivps25constrainsdigitnumberbyendosomemediatedselectivemodulationoffgfshhsignaling |