Placental circadian lincRNAs and spontaneous preterm birth
Frontiers in Genetics2023
Long non-coding RNAs (lncRNAs) have a much higher cell- and/or tissue-specificity compared to mRNAs in most cases, making them excellent candidates for therapeutic applications to reduce off-target effects. Placental long non-coding RNAs have been investigated in the pathogenesis of preeclampsia (often causing preterm birth (PTB)), but less is known about their role in preterm birth. Preterm birth occurs in 11% of pregnancies and is the most common cause of death among infants in the world.
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Co-alterations of circadian clock gene transcripts in human placenta in preeclampsia
Scientific Reports2022
Pre-eclampsia (PE) is a hypertensive condition that occurs during pregnancy and complicates up to 4% of pregnancies. PE exhibits several circadian-related characteristics, and the placenta possesses a functioning molecular clock. We examined the associations of 17 core circadian gene transcripts in placenta with PE vs. non-PE (a mixture of pregnant women with term, preterm, small-for-gestational-age, or chorioamnionitis) using two independent gene expression datasets: GSE75010-157 (80 PE vs. 77 non-PE) and GSE75010-173 (77 PE and 96 non-PE).
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Transcriptional interaction between cFOS and the homeodomain-binding transcription factor VAX1 on the GnRH promoter controls Gnrh1 expression levels in a GnRH neuron maturation specific manner
Molecular and Cellular EndocrinologyHanne M. Hoffmann, Ping Gong, Anika Tamrazian, Pamela L. Mellon
2018
Gonadotropin-releasing hormone (GnRH) is required for pubertal onset and reproduction, thus the control of GnRH transcription is tightly regulated during development and adulthood. GnRH neuron development depends on transcription factors of the homeodomain family. For example, Ventral anterior homeobox 1 (Vax1) is necessary to maintain GnRH expression after embryonic day 13 in the mouse. To further our understanding of the mechanisms by which VAX1 regulates GnRH gene expression, we asked whether VAX1 interacts with other transcription factors to modify GnRH expression levels. Using the GnRH cell lines, GN11 and GT1-7, we found that activation of PKC enhances expression of the immediate early gene cFos in both GN11, and GT1-7, and represses expression of Vax1 in GT1-7. Further, VAX1 interacts with cFOS while bound to the GnRH promoter. In immature GN11 cells, VAX1 and cFOS enhance GnRH expression, whereas VAX1 and cFOS have a repressive role in the mature GT1-7 cells.
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Deletion of Vax1 from Gonadotropin-Releasing Hormone (GnRH) Neurons Abolishes GnRH Expression and Leads to Hypogonadism and Infertility
Journal of NeuroscienceHanne M. Hoffmann, Crystal Trang, Ping Gong, Ikuo Kimura, Erica C. Pandolfi and Pamela L. Mellon
2016
Hypothalamic gonadotropin-releasing hormone (GnRH) neurons are at the apex of the hypothalamic-pituitary-gonadal axis that regulates mammalian fertility. Herein we demonstrate a critical role for the homeodomain transcription factor ventral anterior homeobox 1 (VAX1) in GnRH neuron maturation and show that Vax1 deletion from GnRH neurons leads to complete infertility in males and females. Specifically, global Vax1 knock-out embryos had normal numbers of GnRH neurons at 13 d of gestation, but no GnRH staining was detected by embryonic day 17. To identify the role of VAX1 specifically in GnRH neuron development, Vax1flox mice were generated and lineage tracing performed in Vax1flox/flox:GnRHcre:RosaLacZ mice. This identified VAX1 as essential for maintaining expression of Gnrh1. The absence of GnRH staining in adult Vax1flox/flox:GnRHcre mice led to delayed puberty, hypogonadism, and infertility. To address the mechanism by which VAX1 maintains Gnrh1 transcription, the capacity of VAX1 to regulate Gnrh1 transcription was evaluated in the GnRH cell lines GN11 and GT1-7. As determined by luciferase and electrophoretic mobility shift assays, we found VAX1 to be a direct activator of the GnRH promoter through binding to four ATTA sites in the GnRH enhancer (E1) and proximal promoter (P), and able to compete with the homeoprotein SIX6 for occupation of the identified ATTA sites in the GnRH promoter. We conclude that VAX1 is expressed in GnRH neurons where it is required for GnRH neuron expression of GnRH and maintenance of fertility in mice.
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Dopamine D1-histamine H3 receptor heteromers provide a selective link to the map-kinase signalling in gabaergic neurons of the direct striatal pathway
American Society for Biochemistry and Molecular BiologyMoreno Guillén, Estefanía Hoffmann, Hanne Gonzalez-Sepulveda, Marta Navarro Brugal, Gemma Casadó, Vicent Cortés Tejedor, Antonio Mallol Montero, Josefa Vignes, Michel McCormick, Peter J. Canela Campos, Enric I. Lluís i Biset, Carme Moratalla, Rosario Ferré, Sergi Ortiz, Jordi Franco Fernández, Rafael
2011
Previously, using artificial cell systems, we identified receptor heteromers between the dopamine D1 or D2 receptors and histamine H3 receptor. In addition we demonstrated two biochemical characteristics of the dopamine D1 receptor-histamine H3 receptor heteromer. We have now extended this work to show the dopamine D1 receptor-histamine H3 receptor heteromer exists in the brain and serves to provide a novel link between the Mitogen Activated Protein Kinase (MAPK) pathway and the GABAergic neurons in the direct striatal efferent pathway. Using the biochemical characteristics identified previously we found that the ability of H3 receptor activation to stimulate p44 and p42 extracellular signal-regulated MAP Kinase (ERK 1/2) phosphorylation was only observed in striatal slices of mice expressing D1 receptors but not in D1-receptor-deficient mice. On the other hand, the ability of both D1 and H3 receptor antagonists to block MAPK activation induced by either D1 or H3 receptor agonists was also found in striatal slices. Taken together these data indicate the occurrence of D1-H3 receptor complexes in the striatum and, more importantly, that H3 receptor agonist-induced ERK 1/2 phosphorylation in striatal slices is mediated by D1-H3 receptor heteromers. Moreover, H3 receptor-mediated phospho-ERK 1/2 labeling co-distributed with D1-receptor-containing but not with D2-receptor-containing striatal neurons. These results indicate that D1-H3 receptor heteromers work as processors integrating dopamine- and histamine-related signals involved in controlling the function of striatal neurons of the direct striatal pathway.
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Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine's effects
Journal of NeuroscienceEstefanía Moreno, David Moreno-Delgado, Gemma Navarro, Hanne M Hoffmann, Silvia Fuentes, Santi Rosell-Vilar, Paola Gasperini, Mar Rodríguez-Ruiz, Mireia Medrano, Josefa Mallol, Antoni Cortés, Vicent Casadó, Carme Lluís, Sergi Ferré, Jordi Ortiz, Enric Canela, Peter J McCormick
2014
The general effects of cocaine are not well understood at the molecular level. What is known is that the dopamine D1 receptor plays an important role. Here we show that a key mechanism may be cocaine's blockade of the histamine H3 receptor-mediated inhibition of D1 receptor function. This blockade requires the σ1 receptor and occurs upon cocaine binding to σ1-D1-H3 receptor complexes. The cocaine-mediated disruption leaves an uninhibited D1 receptor that activates Gs, freely recruits β-arrestin, increases p-ERK 1/2 levels, and induces cell death when over activated. Using in vitro assays with transfected cells and in ex vivo experiments using both rats acutely treated or self-administered with cocaine along with mice depleted of σ1 receptor, we show that blockade of σ1 receptor by an antagonist restores the protective H3 receptor-mediated brake on D1 receptor signaling and prevents the cell death from elevated D1 receptor signaling. These findings suggest that a combination therapy of σ1R antagonists with H3 receptor agonists could serve to reduce some effects of cocaine.
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Interactions between intracellular domains as key determinants of the quaternary structure and function of receptor heteromers
Journal of Biological ChemistryGemma Navarro, Sergi Ferré, Arnau Cordomi, Estefania Moreno, Josefa Mallol, Vicent Casadó, Antoni Cortés, Hanne Hoffmann, Jordi Ortiz, Enric I Canela, Carme Lluís, Leonardo Pardo, Rafael Franco, Amina S Woods
2010
G protein-coupled receptor (GPCR) heteromers are macromolecular complexes with unique functional properties different from those of its individual protomers. Little is known about what determines the quaternary structure of GPCR heteromers resulting in their unique functional properties. In this study, using resonance energy transfer techniques in experiments with mutated receptors, we provide for the first time clear evidence for a key role of intracellular domains in the determination of the quaternary structure of GPCR heteromers between adenosine A2A, cannabinoid CB1, and dopamine D2 receptors. In these interactions, arginine-rich epitopes form salt bridges with phosphorylated serine or threonine residues from CK1/2 consensus sites. Each receptor (A2A, CB1, and D2) was found to include two evolutionarily conserved intracellular domains to establish selective electrostatic interactions with intracellular domains of the other two receptors, indicating that these particular electrostatic interactions constitute a general mechanism for receptor heteromerization. Mutation experiments indicated that the interactions of the intracellular domains of the CB1 receptor with A2A and D2 receptors are fundamental for the correct formation of the quaternary structure needed for the function (MAPK signaling) of the A2A-CB1-D2 receptor heteromers. Analysis of MAPK signaling in striatal slices of CB1 receptor KO mice and wild-type littermates supported the existence of A1-CB1-D2 receptor heteromer in the brain. These findings allowed us to propose the first molecular model of the quaternary structure of a receptor heteromultimer.
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