Prolactin receptors (PRLRs) are widely expressed, and multiple mRNA transcripts encoding PRLRs are present in prolactin target tissues. The molecular basis for the control of the PRLR gene expression is currently unknown. Analyses of the 5`-untranslated regions of PRLR mRNAs expressed in gonadal and non-gonadal tissues and their genomic organization revealed three alternative first exons designated as E1, E1, and E1. Each of these exons is alternatively spliced to a common noncoding exon (exon 2, nucleotides -115 to -56) that precedes the third exon containing the translation initiation codon. Alternative utilization of exons E1, E1, and E1, as well as alternative splicing of exon 2, generates multiple 5`-untranslated regions in PRLR transcripts. These alternative first exons (E1, E1, and E1) were found to be utilized in a tissue-specific manner in vivo. E1 is predominantly expressed in the ovary, E1 is specifically expressed in the liver, and E1 is expressed as a predominant form in the Leydig cell and as a minor form in the ovary and liver. Genomic 5`-flanking regions containing the three putative PRLR gene promoters (PI, PII, and PIII) that initiate the transcription of E1, E1, and E1, respectively, were identified. E1 was found to initiate from a single site at -549, E1 from multiple sites at -405, -461, and -506, and E1 from two major sites at -340 and -351. These findings indicate that multiple promoters control transcription of the PRLR gene and provide a molecular basis for the differential regulation of PRLR expression in diverse tissues.

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