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 3rd pharyngeal 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 2nd pouch to transform it to a 3 rd pouch identity and fate; and 4) Test whether Hoxa3 is required for maintenance of Gcm2 and Foxnl expression, using a conditional Hoxa3 allele.
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