Knockout of PI4-Kinase A in GnRH Neurons Causes their Prepubertal Death

Abstract

The signaling pathways that control embryonic development, migration, and differentiation of gonadotropin-releasing hormone (GnRH) neurons, as well as the postnatal fate, function, and survival of differentiated cells, are the subject of ongoing research. Here, we examined the role of phosphoinositides in this complex multistep process by generating GnRH neuron-specific phosphatidylinositol 4-kinase alpha knockout mice. These mice were healthy and indistinguishable from their control littermates in size. However, adult knockout females and males were infertile due to underdeveloped gonads and reproductive organs. Furthermore, hypothalamic GnRH immunoreactivity was absent, and expression of the hypothalamic Gnrh1 gene and pituitary gonadotroph-specific genes was reduced. In contrast, hypothalamic kisspeptin immunoreactivity was preserved, and Kiss1 expression was modified in a nuclei specific-manner, consistent with the loss of circulating sex steroid hormones. Embryonic neurogenesis and migration of GnRH neurons were not impaired, as evidenced by normal Gnrh1 expression in the hypothalamus of neonatal animals and the presence of immunoreactive GnRH neurons in infantile mice in comparable number and distribution to age-matched controls. However, their cellular degeneration was evident, accompanied by reduced Gnrh1 expression. GnRH neuron-specific tdTomato expression confirmed their postnatal degeneration and death, whereas ectopic tdTomato cells located in the lateral septum remained unaffected. Together, these findings indicate that phosphoinositides dependent on phosphatidylinositol 4-kinase alpha activity are not critical for embryonic steps in the development of the GnRH neuronal network, but are essential for the postnatal function and survival of these cells. Significance StatementDifferentiation of neuroendocrine GnRH cells involves neurogenesis in the olfactory placodes, migration to the hypothalamus, projection to the median eminence, and connections with upstream neurons, including kisspeptin neurons. Here we show that knockout of phosphatidylinositol 4-kinase alpha in GnRH neurons does not affect these strps of embryonic development. However, the activity of this enzyme is essential for postnatal survival of GnRH neurons; in the absence of this gene, the neurons die, causing infertility in both female and male mice.