title: Identification of TMEM131L as a novel regulator of thymocyte proliferation in humans.
abstract: In this study, we identify transmembrane protein 131-like (TMEM131L) as a novel regulator of thymocyte proliferation and demonstrate that it corresponds to a not as yet reported inhibitor of Wnt signaling. Short hairpin RNA-mediated silencing of TMEM131L in human CD34(+) hematopoietic progenitors, which were then grafted in NOD-SCID/IL-2rγ(null) mice, resulted in both thymocyte hyperproliferation and multiple pre- and post-β-selection intrathymic developmental defects. Consistent with deregulated Wnt signaling, TMEM131L-deficient thymocytes expressed Wnt target genes at abnormally high levels, and they displayed both constitutive phosphorylation of Wnt coreceptor LRP6 and β-catenin intranuclear accumulation. Using T cell factor reporter assays, we found that membrane-associated TMEM131L inhibited canonical Wnt/β-catenin signaling at the LRP6 coreceptor level. Whereas membrane-associated TMEM131L did not affect LRP6 expression under basal conditions, it triggered lysosome-dependent degradation of its active phosphorylated form following Wnt activation. Genetic mapping showed that phosphorylated LRP6 degradation did not depend on TMEM131L cytoplasmic part but rather on a conserved extracellular domain proximal to the membrane. Collectively, these data indicate that, during thymopoiesis, stage-specific surface translocation of TMEM131L may regulate immature single-positive thymocyte proliferation arrest by acting through mixed Wnt-dependent and -independent mechanisms.
authors.affiliation: Laboratoire Développement du Système Immunitaire de l'Ecole Pratique des Hautes Etudes, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 75571 Paris, France.
authors.forename: Nesrine
authors.initials: N
authors.lastname: Maharzi
authors.forename: Véronique
authors.initials: V
authors.lastname: Parietti
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Nelson
authors.forename: Simona
authors.initials: S
authors.lastname: Denti
authors.forename: Macarena
authors.initials: M
authors.lastname: Robledo-Sarmiento
authors.forename: Niclas
authors.initials: N
authors.lastname: Setterblad
authors.forename: Aude
authors.initials: A
authors.lastname: Parcelier
authors.forename: Marika
authors.initials: M
authors.lastname: Pla
authors.forename: François
authors.initials: F
authors.lastname: Sigaux
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Gluckman
authors.forename: Bruno
authors.initials: B
authors.lastname: Canque
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060168:Thymocytes / Q000166:cytology* / Q000276:immunology; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; C582754:TMEM131L protein, human