DEVELOPMENTAL UP-REGULATION OF HUMAN PARATHYROID-HORMONE (PTH) PTH-RELATED PEPTIDE RECEPTOR GENE-EXPRESSION FROM CONSERVED AND HUMAN-SPECIFIC PROMOTERS

The parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PT HR) functions in skeletal development and mediates an array of other p hysiological responses modulated by PTH and PTHrP. PTHR gene transcrip tion in mouse is controlled by two promoters: P1, which is highly and selectively active in kidney; and P2, which functions in a variety of tissues, pi and P2 are conserved in human tissue; however, P1 activity in kidney is weak. We have now identified a third human promoter, P3, which is widely expressed and accounts for similar to 80% of renal PT HR transcripts in the adult. No P3 activity was detected in mouse kidn ey, indicating that renal PTHR gene expression is controlled by differ ent signals in human and mouse, During development, only P2 is active at midgestation in many human tissues, including calvaria and long bon e, This strongly suggests that factors regulating well conserved P2 co ntrol PTHR gene expression during skeletal development, Our results in dicate that human PTHR gene transcription is upregulated late in devel opment with the induction of both P1 and P3 promoter activities, In ad dition, P2-specific transcripts are differentially spliced in a number of human cell lines and adult tissues, but not in fetal tissues, givi ng rise to a shorter and less structured 5' UTR. Thus, our studies sho w that both human PTHR gene transcription and mRNA splicing are develo pmentally regulated. Moreover, our data indicate that renal and nonren al PTHR gene expression are tightly coordinated in humans.