Adjunct Faculty Ph.D. (1989) Massachusetts Institute of Technology 2015 Distinguished Research Professor Fellow, American Academy of Arts and Sciences Grant Support - “Molecular mechanisms and epigenetic signatures that specify thymus fate” NIH/NIAID “A pilot forward genetic screen for genes affecting thymus involution” NIH/NIAID “Phenotypic and functional investigation of early stage thymic involution” NIH/NIA 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.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. Current interests include understaning the molecular mechanisms controlling the switch from fetal growth to postnatal homeostasis.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. We are also using this knowledge to develop methods for generating cells and organs that may ultimately be used for therapeutic purposes. These insights are leading to developing new approaches to rejuvenating the old thymus, or replacing the old thymus with organs generated in culture. Research Research Areas: Developmental Biology Molecular Genetics Selected Publications Selected Publications: A Sornborger, J Li, C Timmons, Y Takahama, and NR Manley. (2017) “MiCASA: A new method for quantifying tissue organization.” Nature Communications, in press V Bain, J Gordon, JD O’Neil, I Ramos, ER Richie, and NR Manley. (2016) “Tissue-specific roles for Sonic hedgehog signaling in establishing thymus and parathyroid organ fate.” Development, 143(21):4027-4037. PMID:27633995JL 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 thV Bain, J Gordon, JD O’Neil, I Ramos, ER Richie, and NR Manley. (2016) “Tissue-specific roles for Sonic hedgehog signaling in establishing thymus and parathyroid organ fate.” Development, 143(21):4027-4037. PMID:27633995e 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.