Kisspeptins and the Neuroendocrine Control of Reproduction: Recent Progress and New Frontiers in Kisspeptin Research

Frontiers in Neuroendocrinology

2022 Jan 01

Sobrino, V;Soledad, M;Perdices-López, C;Jimenez-Puyer, M;Tena-Sempere, M;
| DOI: 10.1016/j.yfrne.2021.100977

In late 2003, a major breakthrough in our understanding of the mechanisms that govern reproduction occurred with the identification of the reproductive roles of kisspeptins, encoded by the Kiss1 gene, and their receptor, Gpr54 (aka, Kiss1R). The discovery of this unsuspected reproductive facet attracted an extraordinary interest and boosted an intense research activity, in human and model species, that, in a relatively short period, established a series of basic concepts on the physiological roles of kisspeptins. Such fundamental knowledge, gathered in these early years of kisspeptin research, set the scene for the more recent in-depth dissection of the intimacies of the neuronal networks involving Kiss1 neurons, their precise mechanisms of regulation and the molecular underpinnings of the function of kisspeptins as pivotal regulators of all key aspects of reproductive function, from puberty onset to pulsatile gonadotropin secretion and the metabolic control of fertility. While no clear temporal boundaries between these two periods can be defined, in this review we will summarize the most prominent advances in kisspeptin research occurred in the last ten years, as a means to provide an up-dated view of the state of the art and potential paths of future progress in this dynamic, and ever growing domain of Neuroendocrinology.

Type I Interferon Signaling Increases Versican Expression and Synthesis in Lung Stromal Cells During Influenza Infection

The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society

2021 Nov 01

Brune, JE;Chang, MY;Altemeier, WA;Frevert, CW;
PMID: 34666527 | DOI: 10.1369/00221554211054447

Versican, a chondroitin sulfate proteoglycan, is an essential component of the extracellular matrix (ECM) in inflammatory lung disease. Versican's potential as an immunomodulatory molecule makes it a promising therapeutic target for controlling host immune responses in the lungs. To establish changes to versican expression and accumulation during influenza A viral pneumonia, we document the temporal and spatial changes to versican mRNA and protein in concert with pulmonary inflammatory cell infiltration. These studies were performed in the lungs of wild-type C57BL6/J mice on days 3, 6, 9, and 12 post-infection with influenza A virus using immunohistochemistry, in situ hybridization, and quantitative digital pathology. Using duplex in situ hybridization, we demonstrate that type I interferon signaling contributes significantly to versican expression in lung stromal cells. Our findings show that versican is a type I interferon-stimulated gene in pulmonary fibroblasts and pericytes in the context of viral pneumonia. These data also provide a guide for future studies to determine the role of versican in the pulmonary immune response to influenza infection.

CCL2-CCR2 signaling in the skin drives surfactant-induced irritant contact dermatitis via IL-1β-mediated neutrophil accumulation

The Journal of investigative dermatology

2021 Sep 21

Shibuya, R;Ishida, Y;Hanakawa, S;Kataoka, TR;Takeuchi, Y;Murata, T;Akagi, A;Chow, Z;Kogame, T;Nakamizo, S;Nakajima, S;Egawa, G;Nomura, T;Kambe, N;Kitoh, A;Kabashima, K;
PMID: 34560074 | DOI: 10.1016/j.jid.2021.07.182

Surfactant-induced cumulative irritant contact dermatitis (ICD) is a common and clinically important skin disorder. CCL2 is known to mediate inflammation following tissue damage in various organs. Thus, we investigated whether and how CCL2 contributes to the development of murine cumulative ICD induced by a common surfactant, sodium dodecyl sulfate (SDS). Wild-type mice treated topically with SDS for 6 consecutive days developed skin inflammation that recapitulated the features of human cumulative ICD, including barrier disruption, epidermal thickening, and neutrophil accumulation. CCL2 was upregulated in SDS-treated skin, and local CCL2 blockade attenuated SDS-induced ICD. SDS-induced ICD and neutrophil accumulation were also attenuated in mice deficient in CCR2, the receptor for CCL2. Neutrophil depletion alleviated SDS-induced ICD, suggesting that impaired neutrophil accumulation was responsible for the amelioration of ICD in CCR2-deficient mice. In RNA-seq analyses of SDS-treated skin, the expression levels of Il1b in CCR2-deficient mice were highly downregulated compared with those in wild-type mice. Furthermore, the intradermal administration of IL-1β in the SDS-treated skin of CCR2-deficient mice restored the local accumulation of neutrophils and the development of ICD. Collectively, our results suggest that CCL2-CCR2 signaling in the skin critically promotes the development of SDS-induced ICD by inducing IL-1β expression for neutrophil accumulation.

Cannabinoid receptor 2 deletion influences social memory and synaptic architecture in the hippocampus

Scientific reports

2021 Aug 19

Komorowska-Müller, JA;Ravichandran, KA;Zimmer, A;Schürmann, B;
PMID: 34413398 | DOI: 10.1038/s41598-021-96285-9

Although the cannabinoid receptor 2 (CB2R) is often thought to play a role mainly outside the brain several publications unequivocally showed the presence of CB2R on hippocampal principal neurons. Activation of CB2R produced a long-lasting membrane potential hyperpolarization, altered the input/output function of CA2/3 principal neurons and produced alterations in gamma oscillations. However, other cellular, molecular and behavioral consequences of hippocampal CB2R signaling have not been studied in detail. Here we demonstrate that the deletion of CB2 leads to a highly significant increase in hippocampal synapsin-I expression levels and particle density, as well as increased vesicular GABA transporter (vGAT) levels. This phenotype was restricted to females and not observed in males. Furthermore, we demonstrate an impairment of social memory in CB2 deficient mice. Our results thus demonstrate that the lack of CB2R leads to changes in the hippocampal synaptic landscape and reveals an important sex-specific difference in endocannabinoid signaling. This study supports a significant role of the CB2R in modulation of different types of memory despite its low expression levels in the brain and provides more insight into a sex-specific role of CB2R in synaptic architecture.

ADAMTS18 deficiency leads to preputial gland hypoplasia and fibrosis in male mice

Reproductive biology

2021 Aug 10

Lin, X;Wu, T;Wang, L;Dang, S;Zhang, W;
PMID: 34388417 | DOI: 10.1016/j.repbio.2021.100542

ADAMTSs (A disintegrin and metalloproteinase with thrombospondin motifs) are a family of 19 secreted zinc metalloproteinases that play a major role in the assembly and degradation of the extracellular matrix (ECM) during development, morphogenesis, tissue repair, and remodeling. ADAMTS18 is a poorly characterized member of the ADAMTS family. Previously, ADAMTS18 was found to participate in the development of female reproductive tract in mice. However, whether ADAMTS18 also plays a role in the development of male reproductive system remains unclear. In this study, Adamts18 mRNA was found to be highly expressed in the basal cells of the developing preputial gland. Male Adamts18 knockout (Adamts18-/-) mice exhibit abnormal preputial gland morphogenesis, including reduced size and sharp outline. Histological analyses of preputial gland from 2-week-old male Adamts18-/- mice showed significant atrophy of the whole gland. Preputial glands from 7 months and older Adamts18-/- mice appeared macroscopic swelling on their surface. Histologically, preputial gland swelling is characterized by tissue fibrosis and thicker keratinized squamous cell layer. Preputial gland lesions in age-matched male Adamts18+/+ mice were barely detected. ADAMTS18 deficiency does not lead to significant changes in morphogenesis of prostate and testis in male mice. These results indicate that ADAMTS18 is required for normal morphogenesis and homeostasis of the preputial gland in male mice.

Increased Expression of Heparan Sulfate 6-O-Sulfotransferase-2 Promotes Collagen Production in Cardiac Myofibroblasts

BPB Reports

2021 Jun 06

Kasai, K;Horii, Y;Hironaka, T;Mae, K;Ueno, T;Nagasaka, A;Nakaya, M;
| DOI: 10.1248/bpbreports.4.3_85

Fibrosis is defined as the excessive accumulation of extracellular matrix (ECM) proteins. These excessive ECM proteins are produced by myofibroblasts, which are differentiated mainly from resident fibroblasts in response to tissue injury. In addition to the ECM proteins, the amounts of heparan sulfate, one of the sugar chains, and the proteoglycans attached with heparan sulfate chains are reported to be increased in the fibrotic tissues. However, the contribution of heparan sulfate and heparan sulfate proteoglycans to the development of fibrosis remains unclear. In this study, we found that heparan sulfate 6-O-sulfotransferase-2 (Hs6st2), a type of heparan sulfate transferase, is remarkably induced during fibrosis in the heart, liver, and kidney of mice. We also demonstrated that Hs6st2 was specifically expressed in myofibroblasts of mice with cardiac and liver fibrosis. Hs6st2 knockdown in cardiac myofibroblasts reduced the mRNA expression of fibrosis-related factors, such as Collagen1a1. In summary, this study revealed that Hs6st2 is specifically expressed in myofibroblasts in fibrotic tissues, promotes fibrosis, and can be a good target for the treatment for fibrosis.

NDNF interneurons in layer 1 gain-modulate whole cortical columns according to an animal\'s behavioral state

Neuron

2021 May 18

Cohen-Kashi Malina, K;Tsivourakis, E;Kushinsky, D;Apelblat, D;Shtiglitz, S;Zohar, E;Sokoletsky, M;Tasaka, GI;Mizrahi, A;Lampl, I;Spiegel, I;
PMID: 34038743 | DOI: 10.1016/j.neuron.2021.05.001

Processing of sensory information in neural circuits is modulated by an animal's behavioral state, but the underlying cellular mechanisms are not well understood. Focusing on the mouse visual cortex, here we analyze the role of GABAergic interneurons that are located in layer 1 and express Ndnf (L1 NDNF INs) in the state-dependent control over sensory processing. We find that the ongoing and sensory-evoked activity of L1 NDNF INs is strongly enhanced when an animal is aroused and that L1 NDNF INs gain-modulate local excitatory neurons selectively during high-arousal states by inhibiting their apical dendrites while disinhibiting their somata via Parvalbumin-expressing interneurons. Because active NDNF INs are evenly spread in L1 and can affect excitatory neurons across all cortical layers, this indicates that the state-dependent activation of L1 NDNF INs and the subsequent shift of inhibition in excitatory neurons toward their apical dendrites gain-modulate sensory processing in whole cortical columns.

Zona glomerulosa derived Klotho does not regulate aldosterone synthesis in young mice

Endocrine Abstracts

2021 May 15

Tang, C;Xie, Y;Scapin, A;Loffing, D;Breault, D;Loffing, J;Beuschlein, F;
| DOI: 10.1530/endoabs.73.aep8

Klotho (Kl), initially identified as an antiaging gene, plays a critical role in the regulation of renal and adrenal dependent fluid homeostasis. A previous study reported that haplodeficiency of Kl in mice resulted in increased aldosterone synthase (CYP11B2) expression, elevated plasma aldosterone and high blood pressure. This phenotype was presumed to result from diminished Kl expression in zona glomerulosa (zG) of the adrenal. To examine whether Kl expressed in zG is indeed a critical regulator of aldosterone synthesis, we generated a tamoxifen-inducible, zG-specific mouse model of KI deficiency by crossing Kl-flox mice with Cyp11b2-CreERT mice (zG-Kl). Tamoxifen-treated Cyp11b2-CreERT animals (zG-Cre) served as controls. Rosa26-mTmG reporter mice were used for Cre-dependent lineage-marking. Two weeks after tamoxifen induction, the specificity of the zG-Cre line was verified using immunofluorescence analysis to show that GFP expression was restricted to the zG. RNAScope _in situ_ hybridization revealed a 65% down-regulation of Kl mRNA expression in zG of zG-Kl mice at 12-weeks of age compared to control mice. Despite this, zG-Kl mice exhibited no difference in adrenal Cyp11b2 expression or plasma aldosterone levels compared to control mice independent of sex. These results suggest that zG-derived Kl _per se_ does not significantly regulate aldosterone synthesis in young adult mice. Further studies are required to investigate the role of adrenal Kl in aldosterone synthesis in aged mice.

The MAL Protein, an Integral Component of Specialized Membranes, in Normal Cells and Cancer

Cells

2021 Apr 30

Rubio-Ramos, A;Labat-de-Hoz, L;Correas, I;Alonso, MA;
PMID: 33946345 | DOI: 10.3390/cells10051065

The MAL gene encodes a 17-kDa protein containing four putative transmembrane segments whose expression is restricted to human T cells, polarized epithelial cells and myelin-forming cells. The MAL protein has two unusual biochemical features. First, it has lipid-like properties that qualify it as a member of the group of proteolipid proteins. Second, it partitions selectively into detergent-insoluble membranes, which are known to be enriched in condensed cell membranes, consistent with MAL being distributed in highly ordered membranes in the cell. Since its original description more than thirty years ago, a large body of evidence has accumulated supporting a role of MAL in specialized membranes in all the cell types in which it is expressed. Here, we review the structure, expression and biochemical characteristics of MAL, and discuss the association of MAL with raft membranes and the function of MAL in polarized epithelial cells, T lymphocytes, and myelin-forming cells. The evidence that MAL is a putative receptor of the epsilon toxin of Clostridium perfringens, the expression of MAL in lymphomas, the hypermethylation of the MAL gene and subsequent loss of MAL expression in carcinomas are also presented. We propose a model of MAL as the organizer of specialized condensed membranes to make them functional, discuss the role of MAL as a tumor suppressor in carcinomas, consider its potential use as a cancer biomarker, and summarize the directions for future research.

The Expression and Function of Human Ribonuclease 4 in the Kidney and Urinary Tract

American journal of physiology. Renal physiology

2021 Apr 05

Bender, KI;Schwartz, LL;Cohen, A;Mosquera Vasquez, C;Murtha, MJ;Eichler, T;Thomas, JP;Jackson, AR;Spencer, JD;
PMID: 33818125 | DOI: 10.1152/ajprenal.00592.2020

Antimicrobial peptides are essential host defense mechanisms that prevent urinary tract infections. Recent studies demonstrate that peptides in the Ribonuclease A Superfamily have antimicrobial activity against uropathogens and protect the urinary tract from uropathogenic Escherichia coli (UPEC). Little is known is about the antibacterial function or expression of Ribonuclease 4 in the human urinary tract. Here, we show that full-length recombinant Ribonuclease 4 peptide and synthetic amino-terminal Ribonuclease 4 peptide fragment have antibacterial activity against UPEC and multi-drug resistant UPEC. RNASE4 transcript expression was detected in human kidney and bladder tissue using quantitative real-time polymerase chain reaction. Immunostaining or in situ hybridization localized Ribonuclease 4 expression to proximal tubules, principal and intercalated cells in the kidney's collecting duct, and the bladder urothelium. Urinary Ribonuclease 4 concentrations were quantified in healthy controls and females with a urinary tract infection history. Compared to controls, urinary RNase 4 concentrations were significantly lower in females with a urinary tract infection history. When Ribonuclease 4 was neutralized in human urine or silenced in vitro using small interfering RNA, urinary UPEC replication or attachment to and invasion of urothelial and kidney medullary cells increased. These data show that Ribonuclease 4 has antibacterial activity against UPEC, is expressed in the human urinary tract, and can contribute to host defense against urinary tract infections.

Habenula GPR139 is associated with fear learning in the zebrafish

Scientific reports

2021 Mar 10

Roy, N;Ogawa, S;Maniam, R;Parhar, I;
PMID: 33692406 | DOI: 10.1038/s41598-021-85002-1

G-protein coupled receptor 139 (GPR139) is an evolutionarily conserved orphan receptor, predominantly expressing in the habenula of vertebrate species. The habenula has recently been implicated in aversive response and its associated learning. Here, we tested the hypothesis that GPR139 signalling in the habenula may play a role in fear learning in the zebrafish. We examined the effect of intraperitoneal injections of a human GPR139-selective agonist (JNJ-63533054) on alarm substance-induced fear learning using conditioned place avoidance paradigm, where an aversive stimulus is paired with one compartment, while its absence is associated with the other compartment of the apparatus. The results indicate that fish treated with 1 µg/g body weight of GPR139 agonist displayed no difference in locomotor activity and alarm substance-induced fear response. However, avoidance to fear-conditioned compartment was diminished, which suggests that the agonist blocks the consolidation of contextual fear memory. On the other hand, fish treated with 0.1 µg/g body weight of GPR139 agonist spent a significantly longer time in the unconditioned neutral compartment as compared to the conditioned (punished and unpunished) compartments. These results suggest that activation of GPR139 signalling in the habenula may be involved in fear learning and the decision-making process in the zebrafish.

Development of Testis Cords and the Formation of Efferent Ducts in Xenopus laevis: Differences and Similarities with Other Vertebrates

Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation

2021 Mar 04

Li, Y;Li, J;Cai, M;Qin, Z;
PMID: 33662961 | DOI: 10.1159/000513416

The knowledge of testis development in amphibians relative to amniotes remains limited. Here, we used Xenopus laevis to investigate the process of testis cord development. Morphological observations revealed the presence of segmental gonomeres consisting of medullary knots in male gonads at stages 52-53, with no distinct gonomeres in female gonads. Further observations showed that cell proliferation occurs at specific sites along the anterior-posterior axis of the future testis at stage 50, which contributes to the formation of medullary knots. At stage 53, adjacent gonomeres become close to each other, resulting in fusion; then (pre-)Sertoli cells aggregate and form primitive testis cords, which ultimately become testis cords when germ cells are present inside. The process of testis cord formation in X. laevis appears to be more complex than in amniotes. Strikingly, steroidogenic cells appear earlier than (pre-)Sertoli cells in differentiating testes of X. laevis, which differs from earlier differentiation of (pre-)Sertoli cells in amniotes. Importantly, we found that the mesonephros is connected to the testis gonomere at a specific site at early larval stages and that these connections become efferent ducts after metamorphosis, which challenges the previous concept that the mesonephric side and the gonadal side initially develop in isolation and then connect to each other in amphibians and amniotes.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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