Genetic analysis of thymus organogenesis

Summary

Principal Investigator: NANCY R contact MANLEY
Abstract: The long term goal of this research is to understand the molecular mechanisms controlling organogenesis of the thymus and parathyroid glands in mice. The thymus and parathyroid glands play essential roles in the development and function of the immune system and the maintenance of calcium homeostasis, respectively. Although these two organs have distinct primary functions, they originate from a common organ primordium that develops bilaterally from the endoderm of the 3rd pharyngeal pouches during embryogenesis. This unique process provides an opportunity to study many aspects of organogenesis, including initiation, patterning, and differentiation. We have begun to elucidate the regulatory pathways that control these processes, using mutant mouse strains defective in specific aspects of thymus/parathyroid organogenesis. Previous work in my laboratory has shown that Hoxa3 is required for thymus and parathyroid development, and that the Hoxa3 and Pax1 transcription factors have synergistic effects on the early stages of thymus/ parathyroid development. We have also shown that the common primordium has two domains marked by the expression of the transcription factors Foxnl, required for thymus development, and Gcm2, required for parathyroid development. This process is controlled at least in part by the Hoxa3-Paxl pathway, and may be maintained by opposing Shh and Bmp signals in the developing primordia. We have developed a new model for the mechanisms controlling early thymus and parathyroid organogenesis. We propose to test the following hypotheses: 1) Gcm2 expression in the developing 3 rapharyngeal pouch regulates the patterning of the pouch endoderm and the division of the primordium into organ-specific domains; and 2) Hoxa3 regulates early and late stages of thymus and parathyroid organogenesis by controlling both initial and sustained Gcm2 and Foxnl expression. The Specific Aims are: 1) Test whether Gcm2 expression is required for the specification and/or survival of parathyroid precursors in the 3 rdpharyngeal pouch before initial formation of the primordium; 2) Test the ability of Gcm2 to establish the boundary between the thymus and parathyroid- specific regions of the shared primordium during early organogenesis; 3) Test whether integration of the Hoxa3 and Shh pathways is required for the correct patterning of the developing 3rd pouch by manipulating Hoxa3 and Shh expression in the 2ndpouch to transform it to a 3 r_pouch identity and fate; and 4) Test whether Hoxa3 is required for maintenance of Gcm2 and Foxnl expression, usin 9 a conditional Hoxa3 allele.
Funding Period: 1999-01-01 - 2009-01-31
more information: NIH RePORT

Top Publications

  1. pmc Thymus-associated parathyroid hormone has two cellular origins with distinct endocrine and immunological functions
    Zhijie Liu
    Department of Genetics, University of Georgia, Athens, Georgia, United States of America
    PLoS Genet 6:e1001251. 2010
  2. pmc Evidence for an early role for BMP4 signaling in thymus and parathyroid morphogenesis
    Julie Gordon
    Department of Genetics, University of Georgia, Athens, GA 30602, USA
    Dev Biol 339:141-54. 2010
  3. ncbi Structure and function of the thymic microenvironment
    Nancy Ruth Manley
    Department of Genetics, Coverdell Center, 500 DW Brooks Drive, University of Georgia, Athens, GA 30602, USA
    Front Biosci (Landmark Ed) 16:2461-77. 2011
  4. ncbi Differential expression of Sonic hedgehog along the anterior-posterior axis regulates patterning of pharyngeal pouch endoderm and pharyngeal endoderm-derived organs
    Billie A Moore-Scott
    Institute for Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912, USA
    Dev Biol 278:323-35. 2005
  5. ncbi Bmp4 and Noggin expression during early thymus and parathyroid organogenesis
    Seema R Patel
    Department of Genetics, University of Georgia, Athens, GA 30602, USA
    Gene Expr Patterns 6:794-9. 2006
  6. pmc Gcm2 is required for the differentiation and survival of parathyroid precursor cells in the parathyroid/thymus primordia
    Zhijie Liu
    Department of Genetics, University of Georgia, Athens, GA 30602, USA
    Dev Biol 305:333-46. 2007
  7. pmc Specific expression of lacZ and cre recombinase in fetal thymic epithelial cells by multiplex gene targeting at the Foxn1 locus
    Julie Gordon
    Department of Genetics, University of Georgia, Athens, GA 30602, USA
    BMC Dev Biol 7:69. 2007
  8. pmc Increased thymus- and decreased parathyroid-fated organ domains in Splotch mutant embryos
    Ann V Griffith
    Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, Science Park Research Division, Smithville, TX 78957, USA
    Dev Biol 327:216-27. 2009

Scientific Experts

  • NANCY R contact MANLEY
  • Julie Gordon
  • Zhijie Liu
  • Ann V Griffith
  • C Clare Blackburn
  • Seema R Patel
  • Billie A Moore-Scott
  • Beth J Kirby
  • Christopher S Kovacs
  • Lizhen Chen
  • Alison Farley
  • Kurt Engleka
  • Carla Carter
  • Aimee Iberg
  • Jonathan A Epstein
  • Ellen R Richie
  • Kim Cardenas
  • Shannon Yu
  • Farah Mahbub

Detail Information

Publications8

  1. pmc Thymus-associated parathyroid hormone has two cellular origins with distinct endocrine and immunological functions
    Zhijie Liu
    Department of Genetics, University of Georgia, Athens, Georgia, United States of America
    PLoS Genet 6:e1001251. 2010
    ....
  2. pmc Evidence for an early role for BMP4 signaling in thymus and parathyroid morphogenesis
    Julie Gordon
    Department of Genetics, University of Georgia, Athens, GA 30602, USA
    Dev Biol 339:141-54. 2010
    ....
  3. ncbi Structure and function of the thymic microenvironment
    Nancy Ruth Manley
    Department of Genetics, Coverdell Center, 500 DW Brooks Drive, University of Georgia, Athens, GA 30602, USA
    Front Biosci (Landmark Ed) 16:2461-77. 2011
    ..This review will summarize the current state of understanding of the composition and organization of thymic microenvironments and the mechanisms that promote their proper development and function...
  4. ncbi Differential expression of Sonic hedgehog along the anterior-posterior axis regulates patterning of pharyngeal pouch endoderm and pharyngeal endoderm-derived organs
    Billie A Moore-Scott
    Institute for Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912, USA
    Dev Biol 278:323-35. 2005
    ..Our data suggest that, as in the posterior gut endoderm, exclusion of Shh expression from developing primordia is required for the proper development of pharyngeal-derived organs...
  5. ncbi Bmp4 and Noggin expression during early thymus and parathyroid organogenesis
    Seema R Patel
    Department of Genetics, University of Georgia, Athens, GA 30602, USA
    Gene Expr Patterns 6:794-9. 2006
    ..This represents the first detailed study of Bmp4 and Noggin expression during the early stages of thymus and parathyroid organogenesis...
  6. pmc Gcm2 is required for the differentiation and survival of parathyroid precursor cells in the parathyroid/thymus primordia
    Zhijie Liu
    Department of Genetics, University of Georgia, Athens, GA 30602, USA
    Dev Biol 305:333-46. 2007
    ..These results suggest that Gcm2 is not required for pouch patterning or to establish the parathyroid domain, but is required for differentiation and subsequent survival of parathyroid cells...
  7. pmc Specific expression of lacZ and cre recombinase in fetal thymic epithelial cells by multiplex gene targeting at the Foxn1 locus
    Julie Gordon
    Department of Genetics, University of Georgia, Athens, GA 30602, USA
    BMC Dev Biol 7:69. 2007
    ..Since the Foxn1 gene is expressed in all presumptive TECs from the early stages of thymus organogenesis and broadly in the adult thymus, it is an ideal locus for driving gene expression in differentiating and mature TECs...
  8. pmc Increased thymus- and decreased parathyroid-fated organ domains in Splotch mutant embryos
    Ann V Griffith
    Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, Science Park Research Division, Smithville, TX 78957, USA
    Dev Biol 327:216-27. 2009
    ....