Targeted Deletion of PTEN in Kisspeptin Cells Results in Brain Region- and Sex-Specific Effects on Kisspeptin Expression and Gonadotropin Release

Abstract

Kisspeptin-expressing neurons in the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC) of the hypothalamus relay hormonal and metabolic information to gonadotropin-releasing hormone neurons, which in turn regulate pituitary and gonadal function. Phosphatase and tensin homolog (PTEN) blocks phosphatidylinositol 3-kinase (PI3K), a signaling pathway utilized by peripheral factors to transmit their signals. However, whether PTEN signaling in kisspeptin neurons helps to integrate peripheral hormonal cues to regulate gonadotropin release is unknown. To address this question, we generated mice with a kisspeptin cell-specific deletion of Pten (Kiss-PTEN KO), and first assessed kisspeptin protein expression and gonadotropin release in these animals. Kiss-PTEN KO mice displayed a profound sex and region-specific kisspeptin neuron hyperthrophy. We detected both kisspeptin neuron hyperthrophy as well as increased kisspeptin fiber densities in the AVPV and ARC of Kiss-PTEN KO females and in the ARC of Kiss-PTEN KO males. Moreover, Kiss-PTEN KO mice showed a reduced gonadotropin release in response to gonadectomy. We also found a hyperactivation of mTOR, a downstream PI3K target and central regulator of cell metabolism, in the AVPV and ARC of Kiss-PTEN KO females but not males. Fasting, known to inhibit hypothalamic kisspeptin expression and luteinizing hormone levels, failed to induce these changes in Kiss-PTEN KO females. We conclude that PTEN signaling regulates kisspeptin protein synthesis in both sexes and that its role as a metabolic signaling molecule in kisspeptin neurons is sex-specific.

The Periventricular Nucleus as a Brain Center Containing Dopaminergic Neurons and Neurons Expressing Individual Enzymes of Dopamine Synthesis

“…Given the fact that occasional neurons containing the enzymes of dopamine synthesis were described in the PeVN, as in the AN, and both nuclei are located in close vicinity and play a key role in the neuroendocrine regulation of reproduction [ 12 , 29 , 30 , 31 , 32 , 33 ], we hypothesized that the PeVN, similar to the AN, is a dopaminergic center containing numerous monoenzymatic and bienzymatic neurons. Therefore, the aim of the present study was to test this hypothesis by accomplishing the following objectives: (1) to obtain evidence that the PeVN contains a significant number of bienzymatic (dopaminergic) neurons and monoenzymatic neurons expressing only TH or only AADC, and to quantify each of the populations; (2) to determine if the PeVN contains L-DOPA as the final synthetic product in monoenzymatic TH neurons, and dopamine as the final product in bienzymatic and monoenzymatic AADC neurons; (3) if monoenzymatic TH and AADC neurons are found in the PeVN, to test whether they synthesize dopamine in co-operation; (4) to study the topographic relations of monoenzymatic and bienzymatic neurons in the PeVN and within the third cerebral ventricle; (5) to determine whether the cerebrospinal fluid contains L-DOPA and dopamine as an indicator of the secretion of L-DOPA by monoenzymatic TH neurons and dopamine by monoenzymatic AADC neurons and bienzymatic (dopaminergic) neurons; (6) to carry out a comparative analysis of the PeVN and AN as dopaminergic centers of the brain containing dopaminergic (bienzymatic) and monoenzymatic TH and AADC neurons, using the data obtained in this and previous studies.…”

Sexual Dimorphism in Kisspeptin Signaling

“…KP expression in the ARC nuclei is regulated by metabolic cues including leptin and insulin [ 168 ]. Thus, metabolic alterations such as obesity and malnutrition, affect the KP expression and the production of GnRH and GPNs [ 169 , 170 ].…”

“…Selective reintroduction of KPR into the GnRH neurons could partially rescue the metabolic phenotypes in both male and female mice, which suggests that hypothalamic KP signaling plays a role in the metabolic regulation [ 174 ]. PTEN is a critical regulator of metabolism, which is a major negative regulator of the PI3K/AKT pathway and plays an important role in both lipid and glucose metabolism [ 168 ]. Targeted deletion of Pten gene in KP neurons increased the activation of mTOR-signaling, the central regulator of metabolism, in both ARC and AVPV nuclei in female mice but not in males [ 168 ].…”

“…PTEN is a critical regulator of metabolism, which is a major negative regulator of the PI3K/AKT pathway and plays an important role in both lipid and glucose metabolism [ 168 ]. Targeted deletion of Pten gene in KP neurons increased the activation of mTOR-signaling, the central regulator of metabolism, in both ARC and AVPV nuclei in female mice but not in males [ 168 ]. Nevertheless, the precise molecular mechanisms that integrate metabolic signals to KP neurons remain largely unclear [ 168 ].…”

“…Targeted deletion of Pten gene in KP neurons increased the activation of mTOR-signaling, the central regulator of metabolism, in both ARC and AVPV nuclei in female mice but not in males [ 168 ]. Nevertheless, the precise molecular mechanisms that integrate metabolic signals to KP neurons remain largely unclear [ 168 ].…”