Neuroanatomy of the Human Hypothalamic Kisspeptin System

Hrabovszky, Erik

doi:10.1159/000356903

Cited by 78 publications

(77 citation statements)

References 125 publications

(341 reference statements)

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“…1I-L). The ARC also contains tyrosine hydroxylase (TH)-positive neurons (Bluet-Pajot et al, 2001;Biebermann et al, 2012;Hrabovszky, 2014), and 15% of these cells are GHRH-neurons (Phelps et al, 2003). Interestingly, we also found that ∼76% of TH + neurons in the ARC express Isl1 at E16.5 and ∼23% of TH + neurons express Isl1 at P56 (Fig.…”

Section: Expression Of Isl1 In Developing Arcuate Nucleus Neuronsmentioning

confidence: 56%

“…Of note, most NPY + AgRP-neurons are known to be GABAergic, whereas most POMC neurons are non-GABAergic (Horvath et al, 1997;Ovesjo et al, 2001;Hentges et al, 2004). There are also other types of GABAergic neurons in the ARC, including a subset of kisspeptinneurons (Hrabovszky, 2014). Interestingly, more GABAergic neurons were observed in E14.5 Isl1 cko mice in comparison with control mice (Fig.…”

Section: Isl1mentioning

confidence: 87%

“…Among the multiple nuclei of the hypothalamus, the arcuate nucleus (ARC) in the mediobasal hypothalamus is particularly important in sensing and processing various peripheral cues. The ARC is a key regulator of these processes because its diverse array of neuronal subpopulations that control energy balance, growth and reproductive behaviors are located adjacent to the third ventricle and the median eminence, making them ideally positioned to interact with both the peripheral blood stream and numerous regions of the brain (Bluet-Pajot et al, 2001;Biebermann et al, 2012;Hrabovszky, 2014). Despite recent advances in our understanding of the physiological roles of distinct arcuate neuronal subpopulations, the gene regulatory program that orchestrates the development of the ARC remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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The LIM-homeobox transcription factor Isl1 plays crucial roles in the development of multiple arcuate nucleus neurons

Lee

2016

Development

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Neurons in the hypothalamic arcuate nucleus relay and translate important cues from the periphery into the central nervous system. However, the gene regulatory program directing their development remains poorly understood. Here, we report that the LIMhomeodomain transcription factor Isl1 is expressed in several subpopulations of developing arcuate neurons and plays crucial roles in their fate specification. Mice with conditional deletion of the Isl1 gene in developing hypothalamus display severe deficits in both feeding and linear growth. Consistent with these results, their arcuate nucleus fails to express key fate markers of Isl1-expressing neurons that regulate feeding and growth. These include the orexigenic neuropeptides AgRP and NPY for specifying AgRP-neurons, the anorexigenic neuropeptide αMSH for POMC-neurons, and two growth-stimulatory peptides, growth hormone-releasing hormone (GHRH) for GHRH-neurons and somatostatin (Sst) for Sst-neurons. Finally, we show that Isl1 directly enhances the expression of AgRP by cooperating with the key orexigenic transcription factors glucocorticoid receptor and brain-specific homeobox factor. Our results identify Isl1 as a crucial transcription factor that plays essential roles in the gene regulatory program directing development of multiple arcuate neuronal subpopulations.

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Section: Expression Of Isl1 In Developing Arcuate Nucleus Neuronsmentioning

confidence: 56%

Section: Isl1mentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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The LIM-homeobox transcription factor Isl1 plays crucial roles in the development of multiple arcuate nucleus neurons

Lee

2016

Development

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“…While homologous KP and NKB neurons are also present in the human infundibular nucleus [6,7], species differences are also likely to exist in the neurotransmitter complement that these neurons use for communication [8]. Notably, morphological studies have found only poor evidence for dynorphin expression in KP-immunoreactive (IR) neurons in the infundibular nucleus of young men [9].…”

Section: Introductionmentioning

confidence: 99%

Hypophysiotropic Gonadotropin-Releasing Hormone Projections Are Exposed to Dense Plexuses of Kisspeptin, Neurokinin B and Substance P Immunoreactive Fibers in the Human: A Study on Tissues from Postmenopausal Women

et al. 2014

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Neuronal populations that synthesize kisspeptin (KP), neurokinin B (NKB) and substance P (SP) in the hypothalamic infundibular nucleus of humans are partly overlapping. These cells are important upstream regulators of gonadotropin-releasing hormone (GnRH) neurosecretion. Homologous neurons in laboratory animals are thought to modulate episodic GnRH secretion primarily via influencing KP receptors on the hypophysiotropic fiber projections of GnRH neurons. To explore the structural basis of this putative axo-axonal communication in humans, we analyzed the anatomical relationship of KP-immunoreactive (IR), NKB-IR and SP-IR axon plexuses with hypophysiotropic GnRH fiber projections. Immunohistochemical studies were carried out on histological samples from postmenopausal women. The neuropeptide-IR axons innervated densely the portal capillary network in the postinfundibular eminence. Subsets of the fibers formed descending tracts in the infundibular stalk, some reaching the neurohypophysis. KP-IR, NKB-IR and SP-IR plexuses intermingled, and established occasional contacts, with hypophysiotropic GnRH fibers in the postinfundibular eminence and through their lengthy course while descending within the infundibular stalk. Triple-immunofluorescent studies also revealed considerable overlap between the KP, NKB and SP signals in individual fibers, providing evidence that these peptidergic projections arise from neurons of the mediobasal hypothalamus. These neuroanatomical observations indicate that the hypophysiotropic projections of human GnRH neurons in the postinfundibular eminence and the descending GnRH tract coursing through the infundibular stalk to the neurohypophysis are exposed to neurotransmitters/neuropeptides released by dense KP-IR, NKB-IR and SP-IR fiber plexuses. Localization and characterization of axonal neuropeptide receptors will be required to clarify the putative autocrine and paracrine interactions in these anatomical regions.

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“…Recent findings strongly suggest that ARC Kp neurons are critical for GnRH pulses [20][21][22][23][24] , whereas AVPV Kp neurons regulate preovulatory GnRH/LH surges [18,19,25] . Although anatomical differences have been observed across species (detailed discussion of the neuroanatomy of kisspeptin system in human is present in this special issue by Hrabovszky [26]), it is now widely accepted that Kp plays a pivotal role in regulating both GnRH pulses and surges in mammals [27] . Although Kp acts within the hypothalamus, several studies showed that peripheral Kp administration can stimulate GnRH neurons [7,[9][10][11][12] , presumably via circumventricular organs such as median eminence or the organum vasculosum of the lamina terminalis [28][29][30] , thus offering attractive therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

Effects and Therapeutic Potentials of Kisspeptin Analogs: Regulation of the Hypothalamic-Pituitary-Gonadal Axis

Matsui¹,

Asami

2014

Neuroendocrinology

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The hypothalamic peptide kisspeptin (metastin), the endogenous ligand of the G protein-coupled receptor KISS1R, plays a critical role in controlling GnRH release from hypothalamic GnRH neurons and thereby regulates hypothalamic-pituitary-gonadal functions. Although the therapeutic potential of kisspeptin is attractive, its susceptibility to proteolytic degradation limits its utility. To overcome this, KISS1R agonists or antagonists as peptide analogs or small molecules have been investigated. Kisspeptin analogs have been most extensively studied by reducing the length of the peptide from the original 54 amino acids to 10 amino acids or less and by substituting key amino acid residues. Also, 2 investigational kisspeptin agonist analogs have been evaluated in clinical studies in men; in agreement with animal studies, abrupt elevations in gonadotropin and testosterone levels were observed as an acute effect, followed by rapid reductions in these hormones as a chronic effect. Some studies of small-molecule KISS1R antagonists have also been published. In this review, we present a brief overview on kisspeptin/KISS1R physiology in reproductive functions and summarize the available knowledge of both agonists and antagonists. We also focus on the kisspeptin agonist analogs by summarizing key pharmacological findings from both clinical and preclinical studies, and discuss their potential therapeutic utility.

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Neuroanatomy of the Human Hypothalamic Kisspeptin System

Cited by 78 publications

References 125 publications

The LIM-homeobox transcription factor Isl1 plays crucial roles in the development of multiple arcuate nucleus neurons

The LIM-homeobox transcription factor Isl1 plays crucial roles in the development of multiple arcuate nucleus neurons

Hypophysiotropic Gonadotropin-Releasing Hormone Projections Are Exposed to Dense Plexuses of Kisspeptin, Neurokinin B and Substance P Immunoreactive Fibers in the Human: A Study on Tissues from Postmenopausal Women

Effects and Therapeutic Potentials of Kisspeptin Analogs: Regulation of the Hypothalamic-Pituitary-Gonadal Axis

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