T he parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PTHR) functions in skeletal development and mediates an array of other physiological responses modulated by PTH and PTHrP. PTHR gene transcription 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. P1 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 approximately 80% of renal PTHR transcripts in the adult. No P3 activity was detected in mouse kidney, indicating that renal PTHR gene expression is controlled by different signals in human and mouse. During development, only P2 is active at midgestation in many human tissues, including calvaria and long bone. This strongly suggests that factors regulating well conserved P2 control PTHR gene expression during skeletal development. Our results indicate that human PTHR gene transcription is upregulated late in development with the induction of both P1 and P3 promoter activities. In addition, P2-specific transcripts are differentially spliced in a number of human cell lines and adult tissues, but not in fetal tissues, giving rise to a shorter and less structured 5' UTR. Thus, our studies show that both human PTHR gene transcription and mRNA splicing are developmentally regulated. Moreover, our data indicate that renal and nonrenal PTHR gene expression are tightly coordinated in humans.