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 thatVacuolar 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 isolateda polydactylous mouse line carrying a hypomorphic mutation of Vps25 (Vps25(ENU)). Unlike Vps25-nullembryos we generated, Vps25(ENU/ENU) mutants survive until late gestation. Their limbs display FGF signaling enhancement and consequent hyperactivation of the FGF-SHH feedback loopcausing polydactyly, whereas WNT and BMPsignaling remain unperturbed. Notably, Vps25(ENU/ENU) Mouse Embryonic Fibroblasts exhibit aberrantFGFR trafficking and degradation; however, SHH signaling is unperturbed. These studies establish that the ESCRT-II machinery selectivelylimits FGF signaling in vertebrate skeletal patterning.
Highlights
Homeostasis of signaling proteins is maintained through sorting and degradation via endosome-mediated vesicular trafficking (MacGurn et al, 2012)
Isolation of 04-014 Mouse Line with Polydactyly through an N-ethyl-N-nitrosourea Mutagenesis Screen and Identification of the ENU-Induced Mutation in the Vps25 Gene By a N-ethyl-N-nitrosourea (ENU) mutagenesis screen, we isolated mouse line 04-014 based on recessive hindlimb polydactyly with variable expressivity (Figure 1A–1D)
We located the mutation within the murine ortholog of yeast Vacuolar protein sorting 25, Vps25, encoding a subunit of the ESCRT-II complex (Babst et al, 2002b; Slater and Bishop, 2006) essential for endosomal protein trafficking (Henne et al, 2011; MacGurn et al, 2012; Rusten et al, 2012) (Figures 1E; Table S1)
Summary
Using a polydactylous mouse line carrying a hypomorphic mutation in the Vps subunit of the ESCRT-II complex, Handschuh et al establish that ubiquitously expressed machineries that sort signaling proteins preferentially regulate, or are rate limiting for, select signaling pathways in different contexts of the developing embryo.
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