PI4-kinase A is essential for survival of the GnRH neurons

The signaling pathways that control embryonic development and migration of gonadotropin-releasing hormone (GnRH) neurons, as well as the postnatal fate and function 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. The knockout mice were indistinguishable from their control littermates at all time points studied. However, adult knockout females and males were infertile, as reflected by the absence of GnRH immunoreactivity and Gnrh1 expression, and reduced expression of pituitary gonadotroph-specific genes, accompanied by underdeveloped gonads and reproductive organs. Kisspeptin immunoreactivity was preserved and Kiss1 expression was modified in a nucleus-specific-manner, consistent with the loss of circulating sex steroid hormones. Embryonic neurogenesis and migration of GnRH neurons were not dramatically 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 distribution to age-matched controls. However, their cellular degeneration was observed in infantile mice, accompanied by reduced Gnrh1 expression. GnRH neuron-specific expression of tdTomato confirmed their postnatal degeneration, leading to their death, while ectopic tdTomato-positive cells located in the lateral septum remained unaffected. These findings indicate that phosphatidylinositol 4-kinase alpha activity is not critical for the establishment of the GnRH neuronal system, in contrast to the survival of GnRH neurons.