(Scanned from the applicant's description): The integrated endocrine functions of the hypothalamus and pituitary and the juxtaposition of their primordia during embryogenesis, suggest that reciprocal inductive interactions are involved in their concerted development. Direct evidence for these interactions has come from experimental embryology and gene targeting experiments in mice. Our long-term goal is to identify and characterize these interactions on the molecular level, to define the signaling molecules involved, and to understand how these signals influence the intrinsic genetic programs in these two tissues. While there is strong evidence for instructive hypothalamic signaling to the pituitary primordium, reciprocal cell-cell signaling from the developing pituitary to the hypothalamus has not been defined, in large part due to lack of informative molecular markers. Studies on the homeobox gene Rpx/Hesx-1 provide a unique opportunity to study this phenomenon. Rpx/Hesx-1 is the earliest known genetic marker for the anterior neural plate and Rathke's pouch, the primordium of the pituitary. Deletion analysis of the Rpx/Hesxl gene in transgenic mice revealed distinct regulatory regions for the expression in the neural plate and Rathke's pouch, as well as an element that directs transgene expression to a region of the hypothalamus that lies in direct contact with Rathke's pouch. In vitro tissue recombination experiments have established that transgene expression requires contact with the pouch. We hypothesize that this inducible expression mirrors cell-cell signaling that normally occurs between Rathke's pouch and the developing hypothalamus, and that the Rpx """"""""inducible"""""""" element may be present in other genes that normally respond to signals emanating from the pouch. The Rpx-lacZ transgenic mice, in combination with the in vitro tissue explant system and mouse mutations that effect the determination, differentiation, or morphogenesis of the pituitary, provide a novel model system for the molecular genetic dissection of inductive cell signaling during the establishment of the hypothalamic-pituitary axis. The following specific aims are proposed: 1) Delineation of the Rpx cis-regulatory elements that govern Rathke's pouch specific expression and the trans-acting factors that bind to them. 2) Determination of the role of Rpx in pituitary development and inductive signaling through generation of an Rpx conditional allele. 3) Identification of the signal(s) produced by Rathke's pouch that elicits expression of Rpx-lacZ and other inducible genes. 4) Molecular characterization of the inducible response of Rpx-lacZ and other inducible genes. This work will lead to a better understanding of human developmental defects of the hypothalamic-pituitary axis.
| Chou, Shen-Ju; Hermesz, Edit; Hatta, Toshihisa et al. (2006) Conserved regulatory elements establish the dynamic expression of Rpx/HesxI in early vertebrate development. Dev Biol 292:533-45 |
| Tetzlaff, Michael T; Bai, Chang; Finegold, Milton et al. (2004) Cyclin F disruption compromises placental development and affects normal cell cycle execution. Mol Cell Biol 24:2487-98 |
| Tetzlaff, Michael T; Yu, Wei; Li, Mamie et al. (2004) Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box protein. Proc Natl Acad Sci U S A 101:3338-45 |
