title: Transgenic expression of numb inhibits notch signaling in immature thymocytes but does not alter T cell fate specification.
abstract: The conserved adaptor protein Numb is an intrinsic cell fate determinant that functions by antagonizing Notch-mediated signal transduction. The Notch family of membrane receptors controls cell survival and cell fate determination in a variety of organ systems and species. Recent studies have identified a role for mammalian Notch-1 signals at multiple stages of T lymphocyte development. We have examined the role of mammalian Numb (mNumb) as a Notch regulator and cell fate determinant during T cell development. Transgenic overexpression of mNumb under the control of the Lck proximal promoter reduced expression of several Notch-1 target genes, indicating that mNumb antagonizes Notch-1 signaling in vivo. However, thymocyte development, cell cycle, and survival were unperturbed by mNumb overexpression, even though transgenic Numb was expressed at an early stage in thymocyte development (CD4(-)CD8(-)CD3(-) cells that were CD44(+)CD25(+) or CD44(-)CD25(+); double-negative 2/3). Moreover, bone marrow from mNumb transgenic mice showed no defects in thymopoiesis in competitive repopulation experiments. Our results suggest that mNumb functions as a Notch-1 antagonist in immature thymocytes, but that suppression of Notch-1 signaling at this stage does not alter gammadelta/alphabeta or CD4/CD8 T cell fate specification.
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Center and Program in Developmental Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Michelle B
authors.initials: MB
authors.lastname: French
authors.forename: Ute
authors.initials: U
authors.lastname: Koch
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Shaye
authors.forename: Melanie A
authors.initials: MA
authors.lastname: McGill
authors.forename: Sascha E
authors.initials: SE
authors.lastname: Dho
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Guidos
authors.forename: C Jane
authors.initials: CJ
authors.lastname: McGlade
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D007605:Juvenile Hormones / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism; D018655:Lymphocyte Count; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011233:Precipitin Tests; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D051381:Rats; D051880:Receptors, Notch; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D007605:Juvenile Hormones; D008565:Membrane Proteins; C497759:N protein, Drosophila; D020033:Protein Isoforms; D051880:Receptors, Notch; C060606:numb protein, Drosophila