Substance P Regulates Puberty Onset and Fertility in the Female Mouse

Simavlı, Serap; Thompson, Iain; Maguire, Caroline; Gill, John C.; Carroll, Rona S.; Wolfe, Andrew; Kaiser, Ursula B.; Navarro, Vı́ctor

doi:10.1210/en.2014-2012

Cited by 54 publications

(58 citation statements)

References 54 publications

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Section: How Do Pharmacological Interventions Take Advantage Of Pamentioning

confidence: 99%

“…Simavli et al [179] found that agonism of NK1 receptors led to early onset of puberty. Similarly, absence of the Tac1 gene (which encodes Substance P) led to delayed puberty onset and subfertility in female mice [179]. Using Tac1 knockout mice, Niedermair et al [180] observed that Substance P deficiency is associated with decreased bone formation.…”

Section: How Do Pharmacological Interventions Take Advantage Of Pamentioning

confidence: 99%

“…Advances in drug delivery methods could potentially remedy this obstacle. The use of exosomes, which are cell secreted lipid-coated vesicles, to deliver drugs across the blood-brain-barrier has recently shown promising results [179 - 181]. By encapsulating the drug within exosomes it is possible to deliver drugs to the CNS that would otherwise have had poor penetration.…”

Section: Five-year Viewmentioning

confidence: 99%

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Transmission pathways and mediators as the basis for clinical pharmacology of pain

Kirkpatrick

McEntire

Smith

et al. 2016

Expert Review of Clinical Pharmacology

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Introduction Mediators in pain transmission are the targets of a multitude of different analgesic pharmaceuticals. This review explores the most significant mediators of pain transmission as well as the pharmaceuticals that act on them. Areas Covered The review explores many of the key mediators of pain transmission. In doing so, this review uncovers important areas for further research. It also highlights agents with potential for producing novel analgesics, probes important interactions between pain transmission pathways that could contribute to synergistic analgesia, and emphasizes transmission factors that participate in transforming acute injury into chronic pain. Expert Commentary This review examines current pain research, particularly in the context of identifying novel analgesics, highlighting interactions between analgesic transmission pathways, and discussing factors that may contribute to the development of chronic pain after an acute injury.

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Section: How Do Pharmacological Interventions Take Advantage Of Pamentioning

confidence: 99%

Section: How Do Pharmacological Interventions Take Advantage Of Pamentioning

confidence: 99%

Section: Five-year Viewmentioning

confidence: 99%

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Transmission pathways and mediators as the basis for clinical pharmacology of pain

Kirkpatrick

McEntire

Smith

et al. 2016

Expert Review of Clinical Pharmacology

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“…The lists of genes with sex-related expression patterns in pituitary and adrenal overlap substantially (40 of the top 200 genes in common) and include several molecules with functions in reproduction or in biological processes with a marked sex bias. Tissue-specific examples include, for pituitary, TAC1, encoding substance P, which regulates puberty onset and fertility 27 and PTGER2 which plays a role in ovulation and fertilization 28 , and, for adrenal, PRL, which stimulates lactation in new mothers, plays a role in social behaviors, and is regulated by adrenal steroids 29 .…”

Section: Multi-tissue Expression Data: Variation By Age and Sexmentioning

confidence: 99%

Genetic variation and gene expression across multiple tissues and developmental stages in a non-human primate

Jasinska

Zelaya

Peterson

et al. 2016

Preprint

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By analyzing multi-tissue gene expression and genome-wide genetic variation data in samples from a vervet monkey pedigree, we generated a transcriptome resource and produced the first catalogue of expression quantitative trait loci (eQTLs) in a non-human primate model. This catalogue contains more genome-wide significant eQTLs, per sample, than comparable human resources, and reveals sex and age-related expression patterns. Findings include a master regulatory locus that likely plays a role in immune function, and a locus regulating hippocampal long non-coding RNAs (lncRNAs), whose expression correlates with hippocampal volume. This resource will facilitate genetic investigation of quantitative traits, including brain and behavioral phenotypes relevant to neuropsychiatric disorders.

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“…In addition to NKB, the SP/NK1R system also participates in the central regulation of the gonadotropic axis, likely via kisspeptin-dependent mechanisms (9, 10). Supporting this contention, ( a ) studies in humans, rabbits and rats showed a central stimulatory role of SP on LH release (11-13); ( b ) Kiss1 neurons are activated by SP (9); ( c ) SP mRNA and protein has been found in the ARC of rodents (10, 14); ( d ) SP immunoreactivity has been detected in Kiss1 and NKB neurons in the human infundibular nucleus (15); ( e ) chronic SP administration advances puberty onset in rodents (16) and ( f ) Tac1 KO mice with congenital absence of SP, display delayed puberty onset and reproductive impairments (16, 17).…”

Section: Introductionmentioning

confidence: 99%

Redundancy in the central tachykinin systems safeguards puberty onset and fertility

León

Fergani

Talbi

et al. 2018

Preprint

Self Cite

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The tachykinin neurokinin B (NKB, Tac2) is critical for GnRH release. NKB signaling deficiency leads to infertility in humans. However, some patients reverse this hypogonadism resembling the fertile phenotype of Tac2KO and Tacr3KO (encoding NKB receptor, NK3R) mice despite the absence of NKB signaling. Here, we demonstrate that in the absence of NKB signaling, other tachykinins (substance P and neurokinin A [NKA], encoded by Tac1) may take over to preserve fertility. The complete absence of tachykinins in Tac1/Tac2KO mice leads to delayed puberty onset in both sexes and infertility in 80% of females (but not males), in contrast to the 100% fertile phenotype of Tac1KO and Tac2KO mice separately. Furthermore, we demonstrate that NKA controls puberty onset and LH release through NKB-independent mechanisms in the presence of sex steroids and NKB-dependent mechanisms in their absence. In summary, tachykinins interact in a coordinated manner to ensure reproductive success in female mice. 54( Figure 1 D). Of note, first estrous is a more accurate marker of puberty onset as it indicates 55 central activation of the gonadotropic axis. Furthermore, in a fertility test in which adult females 56 were mated with proven fertile WT males, only 20% of Tac1/Tac2 KO females were able to deliver 57 pups over a 90-day long period of mating (Figure 1 E). Moreover, the parturition latency of these 58 small portion of Tac1/Tac2 KO females was longer than in WT controls (WT: 21.66 ± 0.66 days; 59Tac1/Tac2 KO: 29.5 ± 0.5 days; **p<0.01 ) (Figure 1 F) and the litter size was significantly smaller 60 than in controls (WT: 7.33 ± 1.08 pups; Tac1/Tac2 KO: 4 ± 0 pups; **p<0.01) (Figure 1 G). This 61 largely infertile phenotype of Tac1/Tac2 KO females is also supported by the reduced number of 62 corpora lutea in their ovaries (WT: 3.5 ± 0.28 CL/ovary; Tac1/Tac2 KO: 0.75 ± 0.25 CL/ovary; 63 ***p<0.001) (Figure 1 H, I) and significantly lower ovarian weight than controls (WT: 18.50 ± 1.70 64 mg; Tac1/Tac2 KO: 10.83 ± 1.63 mg; **p<0.01). Moreover, since previous studies had 65 documented an improvement of estrous cyclicity with age in Tac2KO mice (8), we assessed 66 whether this was also the case in Tac1/Tac2 KO females at a young (3 months) and older (8 67 months) age and observed that, in both cases, KO females failed to show any signs of regular68 estrous cyclicity (Figure 1 J,K). 69 70 2. Tac1/Tac2 KO females display disrupted LH pulses and response to ovariectomy. 71To further characterize the reproductive phenotype of Tac1/Tac2 KO females, LH pulsatility and 72 long-term response to OVX were assessed. As expected, OVX Tac1/Tac2 KO females displayed 73 a severely disrupted LH pulse pattern (fewer pulses) over 150 minutes compared to OVX WT 74 (WT: 3.33 ± 0.56 pulses/150min; Tac1/Tac2 KO: 1.86 ± 0.26 pulses/150min; *p<0.05) (Figure 2 75 A-C). Interestingly, when the response of LH to OVX was assessed, we observed a biphasic 76 response in which LH levels were reduced compared to WT in Tac1/Tac2 KO and Tac2KO 77 females 2 days post OVX; howev...

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Substance P Regulates Puberty Onset and Fertility in the Female Mouse

Cited by 54 publications

References 54 publications

Transmission pathways and mediators as the basis for clinical pharmacology of pain

Transmission pathways and mediators as the basis for clinical pharmacology of pain

Genetic variation and gene expression across multiple tissues and developmental stages in a non-human primate

Redundancy in the central tachykinin systems safeguards puberty onset and fertility

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