A G-protein coupled PTH/PTHrP type-2 receptor (PTH2R) from teleosts and mammals shows significant homology to the vertebrate PTHfPTHrP type-1 receptor (PTH1R). In an effort to isolate the cognate ligand of the PTH2R, a peptide of 39 amino acid residues was purified from the bovine hypothalamus (tuberoinfundibular peptide of 39 residues, bTIP39), which selectively and potently stimulates the mammalian and teleost PTH2R. It therefore appears that TIP39 is the endogenous ligand of the vertebrate PTH2R. Recently, genomic DNA and cDNA sequences for human and murine TIP39 were isolated, the encoded ligands characterized in vitro, and their tissue specific expression identified in many diverse adult neuroendocrine tissues. In addition, the VTH2R has been shown to have a spatial and temporal expression during early development in the kidney, brain, and testis. To date, only several zebrafish putative PTH2R splice variants have been identified; unknown are the identification of genomic regulatory elements for the human and zebrafish PTH2Rs, as well as TIP39. The identification of promoters for TIP39 and the PTH2R may clarify their tissue specific expression and provide significant information regarding the physiological ramifications of this newly discovered endocrine system. To test the hypothesis that the TIP39-PTH2R system has a regulated expression in diverse endocrine and neuronal tissues, this proposal describes the molecular cloning of the gene and transcript for zebrafish TIP39, identification of the corresponding promoters (Specific Aim 1), and functional characterization of zebrafish TIP39 (Specific Aim 2). In addition, this proposal will clone the zebrafish PTH2R gene to determine the regulatory elements, which control the spatial and temporal expression of the PTH2R and the putative splice variants (Specific Aim 3). The novelty and innovation of using zebrafish as an animal model provides a powerful model system to study the role of TIP39 and the PTH2R in development of several neuro-endocrine systems, which may provide further clues for their biological roles in mammals. Therefore, this work will initiate a long-term molecular endocrine and developmental investigation of the role of the TIP39-PTH2R system in early vertebrate development. Furthermore, future studies may be initiated in characterizing the molecular mechanisms regulating the TIP39 and PTH2R gene expression.
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