Abstract
p140Cap, encoded by the gene SRCIN1 (SRC kinase signaling inhibitor 1), is an adaptor/scaffold protein highly expressed in the mouse brain, participating in several pre- and post-synaptic mechanisms. p140Cap knock-out (KO) female mice show severe hypofertility, delayed puberty onset, altered estrus cycle, reduced ovulation, and defective production of luteinizing hormone and estradiol during proestrus. We investigated the role of p140Cap in the development and maturation of the hypothalamic gonadotropic system. During embryonic development, migration of Gonadotropin-Releasing Hormone (GnRH) neurons from the nasal placode to the forebrain in p140Cap KO mice appeared normal, and young p140Cap KO animals showed a normal number of GnRH-immunoreactive (-ir) neurons. In contrast, adult p140Cap KO mice showed a significant loss of GnRH-ir neurons and a decreased density of GnRH-ir projections in the median eminence, accompanied by reduced levels of GnRH and LH mRNAs in the hypothalamus and pituitary gland, respectively. We examined the number of kisspeptin (KP) neurons in the rostral periventricular region of the third ventricle, the number of KP-ir fibers in the arcuate nucleus, and the number of KP-ir punctae on GnRH neurons but we found no significant changes. Consistently, the responsiveness to exogenous KP in vivo was unchanged, excluding a cell-autonomous defect on the GnRH neurons at the level of KP receptor or its signal transduction. Since glutamatergic signaling in the hypothalamus is critical for both puberty onset and modulation of GnRH secretion, we examined the density of glutamatergic synapses in p140Cap KO mice and observed a significant reduction in the density of VGLUT-ir punctae both in the preoptic area and on GnRH neurons. Our data suggest that the glutamatergic circuitry in the hypothalamus is altered in the absence of p140Cap and is required for female fertility.
Highlights
The neuroendocrine control of sexual maturation and reproduction is a critical process, essential for the preservation of species
We reveal a non-cellautonomous function of p140Cap for glutamatergic input on juvenile and adult GonadotropinReleasing Hormone (GnRH) neurons, which is required for efficient female fertility
We report that the loss of the adaptor protein p140Cap is responsible for a striking reproductive defect in female mice, characterized by reduced number of litters, impaired ovulation, absent elevation of E2 and Luteinizing Hormone (LH) during proestrus, and delayed puberty onset
Summary
The neuroendocrine control of sexual maturation and reproduction is a critical process, essential for the preservation of species. The HPG axis is centrally governed by the pulsatile release of Gonadotropin-Releasing Hormone (GnRH) into the pituitary portal system by the GnRH-secreting neurons whose cell bodies, in mice, are scattered within the medial septum (MS), preoptic area (POA), anterior hypothalamic area (AHA), and the organum vasculosum of the lamina terminalis (OVLT) (Jasoni et al, 2009). Defects of GnRH neuron activity or migration are thought to be the primary cellular cause of congenital disorders known as Kallmann Syndrome and Central Hypogonadotropic Hypogonadism, characterized by delayed sexual maturation and hypofertility (Cariboni and Maggi, 2006; Boehm et al, 2015). It has been hypothesized that glutamatergic neurotransmission is critical for both the activation of GnRH neurons at the time of puberty and the modulation of GnRH secretion, required for fertility (Iremonger et al, 2010; Spergel, 2019a). We reveal a non-cellautonomous function of p140Cap for glutamatergic input on juvenile and adult GnRH neurons, which is required for efficient female fertility
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