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.
Evolution of the pharyngeal organs: The thymus and parathyroids are only present in jawed vertebrates. We are 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.
Organogenesis and morphogenesis: Projects include the molecular and cellular control of thymus and parathyroid organogenesis, and crosstalk between thymic epithelial cells and the multiple cell types in the fetal and postnatal thymus.
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.
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 Biology7: 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.
Xiao, S., D.M. Su and N.R. Manley. 2007. Atypical memory phenotype T cells with low homeostatic potential and impaired TCR signaling and regulatory T cell function inFoxn1D/D mutant mice. J. Immunology 179: 8153-8163
Gordon, J., B. Hughes III, D.M. Su, S. Xiao, S.P. Navarre, B.G. Condie and N.R .Manley. 2007. Specific expression of lacZ and cre recombinase in fetal thymic epithelial cells by multiplex gene targeting at the Foxn1 locus. BMC Developmental Biology 7: 69.
Liu, Z., S. Yu and N.R. Manley. 2007. Gcm2 is required for the differentiation and survival of parathyroid precursor cells in the parathyroid/thymus primordia.Developmental Biology 305: 333-346.
Liu, C., F. Saito, Z. Liu, Y. Lei, S. Uehara, P.E. Love, M. Lipp, S. Kondo, N.R. Manley and Y. Takahama. 2006. Coordination between parathyroid and thymic primordia in chemokine-dependent guidance for pre-vascular fetal thymus colonization. Blood 108: 2531-2539.
Patel, S.R., J. Gordon, F Mahbub, C.C. Blackburn and N.R. Manley. 2006. Bmp4 and Noggin expression during early thymus and parathyroid organogenesis. Gene Expression Patterns 6: 794-799.
Moore-Scott, B. and N.R. Manley. 2005. Differential expression of Sonic hedgehog along the anterior posterior axis regulates patterning of pharyngeal pouch endoderm and maintains arch morphology. Developmental Biology 278: 323-335.
Zamisch, M., B. Moore-Scott, D.M. Su, N.R. Manley and E. Richie. 2005. Ontogeny and regulation of IL-7 expressing thymic epithelial cells. J. Immunol. 174: 60-67.
Blackburn, C.C. and N.R. Manley 2004. Developing a new paradigm For thymus organogenesis. Nature Reviews Immunology 4: 278-289.
Gordon, J., V. Wilson, N.F. Blair, N.R. Manley and C.C. Blackburn. 2004. Functional evidence for a single endodermal origin for the thymic epithelium. Nature Immunology5: 546-553.
Su, D.-M., S. Navarre, W.-J. Oh, B.G. Condie and N.R. Manley. 2003. A domain of Foxn1 required for crosstalk-dependent thymic epithelial cell differentiation. Nature Immunology 4: 1128-1135.