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 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.
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
Karen
K
Handschuh
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
Jennifer
J
Feenstra
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
Matthew
M
Koss
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
Elisabetta
E
Ferretti
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
Maurizio
M
Risolino
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
Rediet
R
Zewdu
Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
Michelle A
MA
Sahai
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
Jean-Denis
JD
Bénazet
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
Xiao P
XP
Peng
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.
Michael J
MJ
Depew
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA; Centre for Genomic Regulation (CRG), 08003 Barcelona, Spain.
Laura
L
Quintana
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.
James
J
Sharpe
Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Baolin
B
Wang
Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA.
Heather
H
Alcorn
Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA.
Roberta
R
Rivi
Departments of Biology and Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
Stephen
S
Butcher
Departments of Biology and Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
J Robert
JR
Manak
IFOM-FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
Thomas
T
Vaccari
Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
Harel
H
Weinstein
Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA.
Kathryn V
KV
Anderson
Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA.
Elizabeth
E
Lacy
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: lis2008@med.cornell.edu.
Licia
L
Selleri
D000818:Animals; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D005121:Extremities / Q000254:growth & development; D025461:Feedback, Physiological; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D017689:Polydactyly / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism
D056827:Endosomal Sorting Complexes Required for Transport; D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D033921:Vesicular Transport Proteins; C000599615:vacuolar protein sorting 25 protein, mouse; D005346:Fibroblast Growth Factors