Postnatal Development and Maintenance of Functional Pituitary Gonadotrophs is Dependent on PI4-kinase A.

Postnatal development of functional pituitary gonadotrophs is necessary for maturation of the hypothalamic-pituitary-gonadal axis, puberty, and reproduction. Here we examined the role of PI4-kinase A, which catalyzes the biosynthesis of PI4P, in mouse reproduction by knocking out this enzyme in cells expressing the gonadotropin-releasing hormone (GnRH) receptor. Knockout mice were infertile, reflecting underdeveloped gonads and reproductive tracts and lack of puberty. The number and distribution of hypothalamic GnRH neurons and Gnrh1 expression in postnatal knockouts were not affected, while Kiss1/Kisspeptin expression was increased. Knockout of PI4-kinase A also did not alter embryonic establishment and neonatal development and function of the gonadotroph population. However, during the postnatal period, there was a progressive loss of expression of gonadotroph-specific genes, including Fshb, Lhb, and Gnrhr, accompanied by low gonadotropin synthesis. The postnatal gonadotroph population also progressively declined, reaching approximately 1/3 of that observed in controls at 3 months of age. In these residual gonadotrophs, GnRH-dependent calcium signaling, and calcium-dependent membrane potential changes were lost, but intracellular administration of inositol-1,4,5-trisphosphate rescued this signaling. These results indicate a key role for PI4-kinase A in the postnatal development and maintenance of a functional gonadotroph population.