Fertility-Regulating Kiss1 Neurons Arise from Hypothalamic<i>Pomc</i>-Expressing Progenitors

Sanz, Elisenda; Quintana, Albert; Deem, Jennifer D.; Steiner, Robert A.; Palmiter, Richard D.; McKnight, G. Stanley

doi:10.1523/jneurosci.3614-14.2015

Cited by 91 publications

(101 citation statements)

References 34 publications

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“…Specificity of Cre recombinase expression was determined by TdTomato reporter ( ROSA26Sor -lox-STOP-TdTomato x Pomc -Cre) (Figure 6A–B). TdTomato expression was tightly restricted to DGCs and the arcuate nucleus, consistent with previous reports (McHugh et al, 2007; Sanz et al, 2015). In order to avoid germ line recombination, we bred Pomc -Cre mice onto an Akap7 KO background and crossed the resulting Pomc Cre/+ ; Akap7 +/- mice to Akap7 lox/lox mice to generate Pomc Cre/+ ; Akap7 lox/- (DG-KO) mice.…”

Section: Resultssupporting

confidence: 92%

Targeted deletion of AKAP7 in dentate granule cells impairs spatial discrimination

Jones

Deem

Younts

et al. 2016

eLife

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Protein Kinase A (PKA) mediates synaptic plasticity and is widely implicated in learning and memory. The hippocampal dentate gyrus (DG) is thought to be responsible for processing and encoding distinct contextual associations in response to highly similar inputs. The mossy fiber (MF) axons of the dentate granule cells convey strong excitatory drive to CA3 pyramidal neurons and express presynaptic, PKA-dependent forms of plasticity. Here, we demonstrate an essential role for the PKA anchoring protein, AKAP7, in mouse MF axons and terminals. Genetic ablation of AKAP7 specifically from dentate granule cells results in disruption of MF-CA3 LTP directly initiated by cAMP, and the AKAP7 mutant mice are selectively deficient in pattern separation behaviors. Our results suggest that the AKAP7/PKA complex in the MF projections plays an essential role in synaptic plasticity and contextual memory formation.DOI: http://dx.doi.org/10.7554/eLife.20695.001

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Section: Resultssupporting

confidence: 92%

Targeted deletion of AKAP7 in dentate granule cells impairs spatial discrimination

Jones

Deem

Younts

et al. 2016

eLife

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“…Cre:GFP , and Gnrh GFP have been characterized (24,46,47); Agrp Cre:GFP and Kiss1 Cre:GFP lines were backcrossed to C57BL/6 background more than six generations. We used a combination of male and female animals in this study.…”

Section: Animalsmentioning

confidence: 99%

AgRP to Kiss1 neuron signaling links nutritional state and fertility

Padilla

Qiu

Nestor

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

186

175

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Mammalian reproductive function depends upon a neuroendocrine circuit that evokes the pulsatile release of gonadotropin hormones (luteinizing hormone and follicle-stimulating hormone) from the pituitary. This reproductive circuit is sensitive to metabolic perturbations. When challenged with starvation, insufficient energy reserves attenuate gonadotropin release, leading to infertility. The reproductive neuroendocrine circuit is well established, composed of two populations of kisspeptin-expressing neurons (located in the anteroventral periventricular hypothalamus, Kiss1AVPV, and arcuate hypothalamus, Kiss1ARH), which drive the pulsatile activity of gonadotropin-releasing hormone (GnRH) neurons. The reproductive axis is primarily regulated by gonadal steroid and circadian cues, but the starvation-sensitive input that inhibits this circuit during negative energy balance remains controversial. Agouti-related peptide (AgRP)-expressing neurons are activated during starvation and have been implicated in leptin-associated infertility. To test whether these neurons relay information to the reproductive circuit, we used AgRP-neuron ablation and optogenetics to explore connectivity in acute slice preparations. Stimulation of AgRP fibers revealed direct, inhibitory synaptic connections with Kiss1ARH and Kiss1AVPV neurons. In agreement with this finding, Kiss1ARH neurons received less presynaptic inhibition in the absence of AgRP neurons (neonatal toxin-induced ablation). To determine whether enhancing the activity of AgRP neurons is sufficient to attenuate fertility in vivo, we artificially activated them over a sustained period and monitored fertility. Chemogenetic activation with clozapine N-oxide resulted in delayed estrous cycles and decreased fertility. These findings are consistent with the idea that, during metabolic deficiency, AgRP signaling contributes to infertility by inhibiting Kiss1 neurons.

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“…With this in mind, it is worth noting that half of the ARC Pomc -expressing cells generated during embryogenesis change their cell fate to become non-POMC cells such as AgRP and Kiss1 neurons (Padilla et al, 2010; Sanz et al, 2015). To explore the possibility that AgRP neurons emerging after MSG insult might be derived from descendants of Pomc -expressing cells, we performed a lineage tracing experiment in mice carrying Tg.Pomc-Cre, Ai14(tdTomato), Npy-GFP reporters, with the use of an independently generated Tg.Pomc-Cre line (Xu et al, 2005) that is distinct from the one used previously (Padilla et al, 2010).…”

Section: Resultsmentioning

confidence: 99%

“…Currently, the identities of these post-mitotic precursors are not fully understood, but cells from the Pomc -expressing lineage may represent one source of these cells. Prior studies indicate that half of the embryonic Pomc -expressing precursors subsequently become non-POMC cells, some of which differentiate into AgRP/NPY neurons and Kiss1 neurons in the ARC (Padilla et al, 2010; Sanz et al, 2015). While the mechanism underlying neuronal transdifferentiation in the hypothalamus is currently not known, reprogramming of transcriptional machinery or microRNAs have been implicated to play important roles in trans-differentiation from non-neuronal cells to neurons (Shenoy and Blelloch, 2012; Tsunemoto et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Acute Lesioning and Rapid Repair of Hypothalamic Neurons outside the Blood-Brain Barrier

et al. 2017

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Summary Neurons expressing agouti-related protein (AgRP) are essential for feeding. The majority of these neurons are located outside the blood-brain barrier (BBB), allowing them to directly sense circulating metabolic factors. Here we show that in adult mice, AgRP neurons outside the BBB (AgRPOBBB) were rapidly ablated by peripheral administration of monosodium glutamate (MSG), whereas AgRP neurons inside the BBB and most proopiomelanocortin (POMC) neurons were spared. MSG treatment induced proliferation of tanycytes, the putative hypothalamic neural progenitor cells, but the newly proliferated tanycytes did not become neurons. Intriguingly, AgRPOBBB neuronal number increased within a week after MSG treatment, and newly emerging AgRP neurons were derived from post-mitotic cells including some from the Pomc-expressing cell lineage. Our study reveals that the lack of protection by the BBB renders AgRPOBBB vulnerable to lesioning by circulating toxins, but that the rapid re-emergence of AgRPOBBB is part of a reparative process to maintain energy balance.

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Fertility-Regulating Kiss1 Neurons Arise from HypothalamicPomc-Expressing Progenitors

Cited by 91 publications

References 34 publications

Targeted deletion of AKAP7 in dentate granule cells impairs spatial discrimination

Targeted deletion of AKAP7 in dentate granule cells impairs spatial discrimination

AgRP to Kiss1 neuron signaling links nutritional state and fertility

Acute Lesioning and Rapid Repair of Hypothalamic Neurons outside the Blood-Brain Barrier

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