Origin of a Rapidly Evolving Homeostatic Control System Programming Testis Function

Mammals share common strategies for regulating reproduction, including a conserved hypothalamic-pituitary-gonadal axis; yet, individual species exhibit differences in reproductive performance. In this report, we describe the discovery of a species-restricted homeostatic control system programming testis growth and function. is a member of the prolactin gene family and its protein product (PLP-J) was discovered as a uterine cytokine contributing to the establishment of pregnancy. We utilized mouse mutagenesis of and revealed its involvement in the regulation of the male reproductive axis. The -null male reproductive phenotype was characterized by testiculomegaly and hyperandrogenism. The larger testes in the -null mice were associated with an expansion of the Leydig cell compartment. locus is a template for two transcripts ( and ) expressed in a tissue-specific pattern. is expressed in uterine decidua, while is expressed in Leydig cells of the testis. 5'RACE, chromatin immunoprecipitation and DNA methylation analyses were used to define cell-specific promoter usage and alternative transcript expression. We examined the locus in five murid rodents and showed that the testicular transcript and encoded protein are the result of a recent retrotransposition event at the locus. encodes PLP-J V1 and encodes PLP-J V2. Each protein exhibits distinct intracellular targeting and actions. PLP-J V2 possesses Leydig cell-static actions consistent with the -null testicular phenotype. Analysis of the biology of the gene has provided insight into a previously unappreciated homeostatic setpoint control system programming testicular growth and function.