title: Generation of mice with conditionally activated transforming growth factor beta signaling through the TbetaRI/ALK5 receptor.
abstract: We generated a transgenic mouse strain (LSL-TbetaRI(CA)) containing a latent constitutively active TGFbeta type I receptor (TbetaRI/ALK5) by using a knock-in strategy into the X chromosome-linked hypoxanthine phosphoribosyl-transferase (Hprt) locus. Transgene expression, under the control of the ubiquitous CAG (human cytomegalovirus enhancer and chicken beta-actin) promoter, is repressed by a floxed transcriptional "Stop" (LSL, Lox-Stop-Lox). In the presence of cre-recombinase, the "Stop" is excised to allow TbetaRI(CA) transgene expression. We showed that restricted expression of TbetaRI(CA) in T lymphocytes efficiently activates TGFbeta signaling and rescues the T-cell autoimmune disorders of TGFbetaRII conditional knockouts. Unexpectedly, our study reveals that TGFbeta signaling upregulation controls T-cell activation but does not impair their development or their peripheral homeostasis. In addition to the information provided on TGFbeta effects on T-cell biology, LSL-TbetaRI(CA) mouse constitutes an attractive tool to address the effect of TGFbeta signaling upregulation in any cell type expressing the cre-recombinase.
authors.affiliation: INSERM, U590, INSERM Avenirgroup, Oncogenèse et progression tumorale, Centre Léon Bérard, 28 rue Laënnec, Lyon Cedex 08, France. bartholi@lyon.fnclcc.fr
authors.forename: Laurent
authors.initials: L
authors.lastname: Bartholin
authors.forename: Farhan S
authors.initials: FS
authors.lastname: Cyprian
authors.forename: David
authors.initials: D
authors.lastname: Vincent
authors.forename: Céline N
authors.initials: CN
authors.lastname: Garcia
authors.forename: Sylvie
authors.initials: S
authors.lastname: Martel
authors.forename: Branka
authors.initials: B
authors.lastname: Horvat
authors.forename: Cyril
authors.initials: C
authors.lastname: Berthet
authors.forename: Sophie
authors.initials: S
authors.lastname: Goddard-Léon
authors.forename: Isabelle
authors.initials: I
authors.lastname: Treilleux
authors.forename: Ruth
authors.initials: R
authors.lastname: Rimokh
authors.forename: Julien C
authors.initials: JC
authors.lastname: Marie
mesh_terms: D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008213:Lymphocyte Activation / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse