Axl and Tyro3 Modulate Female Reproduction by Influencing Gonadotropin-Releasing Hormone Neuron Survival and Migration

Abstract

GnRH neurons must undergo a complex and precise pattern of neuronal migration to appropriately target their projections to the median eminence to trigger gonadotropin secretion and thereby control reproduction. Using NLT GnRH cells as a model of early GnRH neuronal development, we identified the potential importance of Axl and Tyro3, members of the TAM (Tyro3, Axl, and Mer) family of receptor tyrosine kinases in GnRH neuronal cell survival and migration. Silencing studies evaluated the role of Tyro3 and Axl in NLT GnRH neuronal cells and suggest that both play a role in Gas6 stimulation of GnRH neuronal survival and migration. Analysis of mice null for both Axl and Tyro3 showed normal onset of vaginal opening but delayed first estrus and persistently abnormal estrous cyclicity compared with wild-type controls. Analysis of GnRH neuronal numbers and positioning in the adult revealed a total loss of 24% of the neuronal network that was more striking (34%) when considered within specific anatomical compartments, with the largest deficit surrounding the organum vasculosum of the lamina terminalis. Analysis of GnRH neurons during embryogenesis identified a striking loss of immunoreactive cells within the context of the ventral forebrain compartment (36%) and not more rostrally. Studies using caspase 3 cleavage as a marker of apoptosis showed that Axl(-/-), Tyro3(-/-) double-knockout mice had increased cell death in the nose and dorsal forebrain, supporting the underlying mechanism of cell loss. Together these data suggest that Axl and Tyro3 mediate the survival and appropriate targeting of GnRH neurons to the ventral forebrain, thereby contributing to normal reproductive function and cyclicity in the female.

The Role of the TAM Family of Receptor Tyrosine Kinases in Neural Development and Disorders

“…GnRH neurons migrate into the brain along olfactory axon fibres from the nose during development [38,39]. All three TAM receptors promote GnRH neuronal cell migration and survival and affect normal female reproductive function [40][41][42]. Patients with idiopathic hypogonadotropic hypogonadism exhibit functional consequences of Axl sequence variants, which indicates the importance of Axl in reproductive development [42].…”

“…Patients with idiopathic hypogonadotropic hypogonadism exhibit functional consequences of Axl sequence variants, which indicates the importance of Axl in reproductive development [42]. The loss of GnRH neurons in Axl/Tyro3 null mice impairs the sex hormone-induced gonadotropin surge and results in estrous cycle abnormalities [40]. Axl/Tyro3 null mice also exhibit reproductive malfunctions [40][41][42].…”

“…The loss of GnRH neurons in Axl/Tyro3 null mice impairs the sex hormone-induced gonadotropin surge and results in estrous cycle abnormalities [40]. Axl/Tyro3 null mice also exhibit reproductive malfunctions [40][41][42]. These reproductive abnormalities in Axl/…”

“…The Role of the TAM Family of Receptor Tyrosine Kinases in Neural Development and Disorders Tyro3 null mice are due to GnRH neuron malfunction in hypothalamic, but not pituitary or ovarian, defects [40][41][42]. The anti-apoptotic effect of Tyro3 or Axl plays a role in mediating the survival and appropriate targeting of GnRH neurons to the ventral forebrain, which contributes to normal reproductive function and cyclicity in the female [40].…”

“…The anti-apoptotic effect of Tyro3 or Axl plays a role in mediating the survival and appropriate targeting of GnRH neurons to the ventral forebrain, which contributes to normal reproductive function and cyclicity in the female [40]. Gas6 null adults and embryos exhibit a diminished GnRH neuronal population, which delays vaginal opening and sexual maturation in mice [42].…”