A functional analysis of growth hormone receptor promoter regions in swine
[EMBARGOED UNTIL 08/01/2026] Growth hormone (GH) and its receptor (GHR) play critical roles in regulating growth, development, and reproductive function in animals. GHR expression in the liver is critical for postnatal growth and is regulated by tissue-specific promoters. While promoter 1 (P1) is considered the primary hepatic promoter in species such as cattle, the role of P1 and promoter 2 (P2) in pigs remains poorly defined. This study used CRISPR/Cas9 to generate pigs with bi-allelic knockouts of either P1 (P1KO) or P2 (P2KO) to evaluate the promoter-specific regulation of hepatic GHR signaling and systemic growth. P1KO pigs exhibited normal hepatic GHR and IGF1 expression, normal circulating GH and IGF1 concentrations, and no differences in postnatal growth compared with wildtype (WT) littermates. In contrast, P2KO pigs showed marked reductions in GHR1B, total GHR, and IGF1 mRNA in both liver and muscle, accompanied by elevated circulating GH and lower IGF1 concentrations compared with WT. These endocrine changes were associated with impaired postnatal growth, with P2KO pigs consistently weighing less than WT animals. Despite this, P2KO females were capable of lactation, though fetal growth and litter size were reduced. These findings suggest that promoter 2, not promoter 1, is the primary regulator of hepatic GHR expression and somatotropic axis coupling in pigs. The results highlight species-specific differences in GHR regulation and underscore the functional importance of promoter 2 in supporting postnatal growth and metabolic function. This study also demonstrates the efficacy of targeted gene editing to dissect promoter-specific gene function in livestock.
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