- 2015 Distinguished Research Professor
- Fellow, American Academy of Arts and Sciences
- Grant Support -
- “Molecular mechanisms and epigenetic signatures that specify thymus fate” NIH/NIAID
- “The role of Notch1 in thymic epithelial cells,” NIH/NIA
- “Mouse models for TB infection across the lifespan,” NIH/NIAID
- “The role of ATF3 in thymus involution, ” NIH/NIAID
- “Studies of Immunosenescence and Other Late Effects of Acute Ionizing Radiation Exposure in Atomic Bomb Survivors,” NIH/NIAID
- “Histopathological evaluation of human thymus architecture changes following radiation exposure and aging,” NIH/NIAID
- Research Interests -
My lab is primarily focused on studying the "life history" of the thymus, the primary lymphoid organ responsible for the generation of T cells. This approach encompasses the evolution, fetal development, postnatal function, and aging of this critical organ. Our basic hypothesis is that these diverse aspects of the biology of the organ are controlled by common regulatory networks, cellular dynamics, and physiological processes. We also study the parathyroid, which is required for calcium homeostasis, and has a shared developmental ontogeny with the thymus. We use a variety of approaches to accomplish these goals, including genetic analysis of tissue-specific and inducible mutant mouse strains, comparative and experimental embryology, and immunological techniques. Several of our current projects include natural and induced cellular fate transformations to generate thymic epithelial cells from heterologous cell types, that are either natural sources of ectopic T cell generation, or may be sources of thymus organs for transplant.
Organogenesis and morphogenesis: Projects include the molecular and cellular control of thymus and parathyroid organogenesis, the generation and maintenance of tissue-specific stem cells, and crosstalk between thymic epithelial cells and the multiple cell types in the fetal and postnatal thymus for the development of a functional organ. We are also using our knowledge of early organogenesis to investigate the evolutionary origins of these organs. This approach may allow us to identify mechanisms by which vertebrates have evolved "newer" functions, such as adaptive immunity, from evolutionarily ancient embryonic structures.
Thymic epithelial cell development and function: Projects are focused primarily on the role of the Foxn1 transcription factor in thymic epithelial cell differentiation and function, during both fetal development and in the postnatal thymus.
Thymic involution and immunosenescence: The thymus is the earliest organ to degenerate, losing much of its structural and functional integrity by early adulthood. This process of involution is a major contributor to immunosenescence. Our work to date suggests that the molecular mechanisms regulating fetal development may provide insight into the mechanisms regulating thymic involution. These insights are leading to developing new approaches to rejuvenating the old thymus, or replacing the old thymus with organs generated in culture.
- JL Chojnowski, K Masuda, HA Trau, K Thomas, M Capecchi, and NR Manley. (2014) Multiple roles for Hoxa3 in regulating thymus and parathyroid differentiation and morphogenesis. Development, Aug;141(15):2950-8. PMID:25053428
- N Bredenkamp, S Ulyanchenko, K O'Neill, NR Manley, H Vaidya, and CC Blackburn. (2014) An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts. Nature Cell Biology, Sep;16(9):902-8 PMID:24990082
- K Reeh, K Cardenas, V Bain, Z. Liu, M Laurent, NR Manley, and ER Richie. (2014) Ectopic TBX1 suppresses thymic epithelial cell differentiation and proliferation during thymus organogenesis. Development, Aug;141(15):2950-8 PMID:25053428
- Li, J, Z Liu, S. Xiao, and NR Manley. (2013) Transdifferentiation of parathyroid cells into cervical thymi promotes atypical T cell development. Nature Communications, Dec 17;4:2959. PMID:24343363
- Bryson, J.L., A.V. Griffith, B. Hughes III, F. Saito, Y. Takahama, E.R. Richie and N.R. Manley. Cell-autonomous defects in thymic epithelial cells disrupt endothelial - perivascular cell crosstalk. PLoS One, in press.
- Garfin, P.M., M. Dullei, J.L. Bryson, T. Serwold, E. Badreddin, C.C. Blackburng, E.R. Richie, K. Weinberg, N.R. Manley, J. Sage and P. Viatour. 2013. Inactivation of the RB family prevents thymus involution and promotes thymic function by direct control of Foxn1 expression. J. Exp. Med., in press.
- Gardiner, J.R., A.L. Jackson, J. Gordon, H. Lickert, N.R. Manley and M.A. Basson. 2012. Localized inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis. Development 139(18): 3456-66.
- Wei, Q., N.R. Manley and B.G. Condie. 2011. Whole mount in situ hybridization of E8.5 to E11.5 mouse embryos. J. Vis Exp. 56: 2797.
- Bryson, J.L., M. Coles and N.R. Manley. 2011. A method for labeling vasculature in embryonic mice. J Vis Exp. 56: e327.
- Liu, Z., L. Chen and N.R. Manley. 2010. Thymus-associated parathyroid hormone has two cellular origins with distinct endocrine and immunological functions. PLoS Genetics 6(12): e1001251.
- Xiao, S. and N.R. Manley. 2010. Impaired thymic selection and abnormal antigen-specific T cell responses in Foxn1Δ/Δ mutant mice. PLoS One 4;5(11): e15396.
- Foster, K., J. Gordon, K. Cardenas, H. Veiga-Fernandes, T. Makinen, V. Pachnis, D. Wilkinson, E. Richie, C.C. Blackburn, N.R. Manley, R. Adams, D. Kioussis and M. Coles. 2010. EphB-Ephrin B2 interactions in the collective migration of thymic primordium during organogenesis. PNAS 107: 13414-9.
- Chen, L., P. Zhao, L. Wells, C.T. Amemiya, B.G. Condie and N.R. Manley. 2010. Mouse and zebrafish Hoxa3 orthologs have non-equivalent in vivo protein function. PNAS 107: 10555-60.
- Gordon, J., S.R. Patel, Y. Mishina and N.R. Manley. 2010. Evidence for an early role for Bmp4 signaling in thymus and parathyroid morphogenesis. Developmental Biology 339: 141-54.
- Fraser, G.J., C.D. Hulsey, R.F. Bloomquist, K. Uyesugi, N.R. Manley and J.T. Streelman. 2009. An ancient gene network is co-opted for teeth on old and new jaws. PLoS Biology 7: e31.
- Griffith, A.V., C. Carter, J. Gordon, A. Iberg, N.R. Manley and E.R. Richie. 2009. Increased thymus- and decreased parathyroid-fated organ domains in Splotch mutant embryos. Developmental Biology 327: 216-27.
- Youm, Y.-H., H. Yang, Y. Sun, R.G. Smith, N.R. Manley, B. Vandanmagsar and V.D. Dixit. 2009. Deficient ghrelin receptor mediated signaling compromises thymic stromal cell microenvironment by accelerating thymic adiposity. J. Biol. Chem. 284: 7068-7077.
- Chen, L., S. Xiao and N.R. Manley. 2009. Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner. Blood 113: 567-74.
- Xiao, S., D.M. Su and N.R. Manley. 2008. T cell development from kit-negative progenitors in the Foxn1D/D mutant thymus. J. Immunology 180: 914-921.
Developmental genetics of vertebrate organogenesis: life history of the thymus (responsible for the generation of T cells); diverse aspects of biology of organ controlled by cellular dynamics, regulatory networks, and physiological processes; organ homeostasis, aging, and regeneration