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María Ángeles Arévalo - One of the best experts on this subject based on the ideXlab platform.
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Interaction of sex chromosome complement, gonadal hormones and neuronal steroid synthesis on the sexual differentiation of mammalian neurons.
Journal of neurogenetics, 2017Co-Authors: MarÃa J. Cambiasso, Isabel Ruiz-palmero, María Ángeles Arévalo, MarÃa J. Scerbo, Carla Daniela Cisternas, Iñigo Azcoitia, Luis-miguel Garcia-seguraAbstract:Female mouse hippocampal and hypothalamic neurons growing in vitro show a faster development of neurites than male mouse neurons. This sex difference in neuritogenesis is determined by higher expression levels of the neuritogenic factor Neurogenin 3 in female neurons. Experiments with the four core genotype mouse model, in which XX and XY animals with male gonads and XX and XY animals with female gonads are generated, indicate that higher levels of Neurogenin 3 in developing neurons are determined by the presence of the XX chromosome complement. Female XX neurons express higher levels of estrogen receptors than male XY neurons. In female XX neurons, neuronal derived estradiol increases Neurogenin 3 expression and neuritogenesis. In contrast, neuronal-derived estradiol is not able to upregulate Neurogenin 3 in male XY neurons, resulting in decreased neuritogenesis compared to female neurons. However, exogenous testosterone increases Neurogenin 3 expression and neuritogenesis in male XY neurons. These findings suggest that sex differences in neuronal development are determined by the interaction of sex chromosomes, neuronal derived estradiol and gonadal hormones.
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Oestradiol synthesized by female neurons generates sex differences in neuritogenesis
Scientific reports, 2016Co-Authors: Isabel Ruiz-palmero, Luis M. Garcia-segura, Ana Ortiz-rodriguez, Roberto C. Melcangi, Donatella Caruso, Gabriele M. Rune, María Ángeles ArévaloAbstract:Testosterone produced by the foetal testis is converted by male neurons to oestradiol, which masculinizes neuronal morphology. Female neurons are known to synthesize oestradiol in absence of exogenous testosterone. However, the role of neuronal oestradiol on the differentiation of foetal female neurons is unknown. Here we show that, due to endogenous neuronal oestradiol synthesis, female hippocampal neurons have higher expression of the neuritogenic protein Neurogenin 3 and enhanced neuritogenesis than males. Exogenous application of testosterone or its metabolite dihydrotestosterone increases Neurogenin 3 expression and promotes neuritogenesis in males, but reduces these parameters in females. Together our data indicate that gonadal-independent oestradiol synthesis by female neurons participates in the generation of sex differences in hippocampal neuronal development.
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g protein coupled estrogen receptor is required for the neuritogenic mechanism of 17β estradiol in developing hippocampal neurons
Molecular and Cellular Endocrinology, 2013Co-Authors: Isabel Ruizpalmero, Luis M Garciasegura, M D Hernando, María Ángeles ArévaloAbstract:Abstract Estradiol promotes neuritogenesis in developing hippocampal neurons by a mechanism involving the upregulation of Neurogenin 3, a Notch-regulated transcription factor. In this study we have explored whether G-protein coupled estrogen receptor 1 (GPER) participates in this hormonal action. GPER agonists (17β-estradiol, G1, ICI 182,780) increased Neurogenin 3 expression and neuritogenesis in mouse primary hippocampal neurons and this effect was blocked by the GPER antagonist G15 and by a siRNA for GPER. In addition, GPER agonists increased Akt phosphorylation in ser473, which is indicative of the activation of phosphoinositide-3-kinase (PI3K). G15 or GPER silencing prevented the estrogenic induction of Akt phosphorylation. Furthermore, the PI3K inhibitor wortmannin prevented the effect of G1 and estradiol on Neurogenin 3 expression and the effect of estradiol on neuritogenesis. These findings suggest that GPER participates in the control of hippocampal neuritogenesis by a mechanism involving the activation of PI3K signaling.
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A CRM1-mediated nuclear export signal is essential for cytoplasmic localization of Neurogenin 3 in neurons.
PloS one, 2013Co-Authors: Julia Simon-areces, Isabel Ruiz-palmero, Estefania Acaz-fonseca, Luis-miguel Garcia-segura, María Ángeles ArévaloAbstract:Neurogenin 3 (Ngn3), a proneural gene, regulates dendritogenesis and synaptogenesis in mouse hippocampal neurons. Ngn3 is transiently exported from the cell nucleus to the cytoplasm when neuronal polarity is initiated, suggesting that the nucleo-cytoplasmic transport of the protein is important for its action on neuronal development. In this study, we identified for the first time a functional nuclear export sequence (NES2; 131YIWALTQTLRIA142) in Ngn3. The green fluorescent protein (EGFP)-NES2 fusion protein was localized in the cytoplasm and its nucleo-cytoplasmic shuttling was blocked by the CRM1 specific export inhibitor leptomycin B. Mutation of a leucine residue to alanine (L135A) in the NES2 motif resulted in both cytoplasmic and nuclear localization of the EGFP-NES2 fusion protein and in the nuclear accumulation of ectopic full-length myc-Ngn3. In addition, point mutation of the leucine 135 counteracted the effects of Ngn3 on neuronal morphology and synaptic inputs indicating that the cytoplasmic localization of Ngn3 is important for neuronal development. Pharmacological perturbation of the cytoskeleton revealed that cytoplasmic Ngn3 is associated with microtubules.
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Estradiol Meets Notch Signaling in Developing Neurons
Frontiers in endocrinology, 2011Co-Authors: María Ángeles Arévalo, Isabel Ruiz-palmero, Julia Simon-areces, Estefania Acaz-fonseca, Iñigo Azcoitia, Luis M. Garcia-seguraAbstract:The transmembrane receptor Notch, a master developmental regulator, controls gliogenesis, neurogenesis and neurite development in the nervous system. Estradiol, acting as a hormonal signal or as a neurosteroid, also regulates these developmental processes. Here we review recent evidence indicating that estradiol and Notch signaling interact in developing hippocampal neurons by a mechanism involving the putative membrane receptor G protein-coupled receptor 30. This interaction is relevant for the control of neuronal differentiation, since the downregulation of Notch signaling by estradiol results in the upregulation of Neurogenin 3, which in turn promotes dendritogenesis.
Michael S. Lan - One of the best experts on this subject based on the ideXlab platform.
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Expression of insulinoma-associated 2 (INSM2) in pancreatic islet cells is regulated by the transcription factors Ngn3 and NeuroD1.
Endocrinology, 2011Co-Authors: Tao Cai, Michael S. Lan, Tao Zhang, Xiang Chen, Rennian Wang, Yuhui You, Abner Louis NotkinsAbstract:The insulinoma-associated 2 (Insm2) gene is a member of the Snail/Gfi1/Insm1 transcriptional repressor superfamily. However, little is known about how the expression of human INSM2 or mouse Insm2 in neuroendocrine tissues is regulated. Here we report the expression of INSM2/Insm2 in human fetal pancreas and mouse embryos, as well as adult pancreatic islets, and its regulation by two major islet transcription factors. Mutagenesis and chromatin immunoprecipitation analysis demonstrated that the proximal E-boxes of the mouse Insm2 promoter are direct targets of Neurogenin 3 and neurogenic differentiation 1 (NeuroD1). Furthermore, we found that endogenous Insm2 expression was activated in Ngn3/NeuroD1-transduced pancreatic epithelial duct cells. Our results suggest that Insm2 plays an important role in the differentiation cascade of Ngn3/NeuroD1 signaling in pancreatic islets.
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Insulinoma-Associated Antigen-1 Zinc-Finger Transcription Factor Promotes Pancreatic Duct Cell Trans-Differentiation
Endocrinology, 2010Co-Authors: Tao Zhang, Mary B. Breslin, Hong-wei Wang, Nicolle A. Saunee, Michael S. LanAbstract:Insulinoma-associated antigen-1 (INSM1/IA-1) is a unique zinc-finger transcription factor restrictedly expressed in pancreatic β-cells during early pancreas development. INSM1 is transiently activated by the islet-specific endocrine factor Neurogenin 3, and it subsequently regulates downstream target genes NeuroD1 and insulin during β-cell maturation. Here, we examined how the INSM1 transcription factor contributes to endocrine cell differentiation using a defined serum-free medium-primed pancreatic duct cell model. We showed that ectopic expression of INSM1 can promote Panc-1 cell trans-differentiation. INSM1 up-regulates two islet transcription factors (ITFs), paired box 6 and homeodomain transcription factor 6.1, whereas other ITFs, including pancreatic duodenal homeobox-1 (Pdx-1), homeodomain transcription factor 2.2, NeuroD1, paired box 4, and Neurogenin 3, were either down-regulated or absent. The result suggests that INSM1 is capable of regulating multiple ITFs and the insulin gene either directly ...
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Neurogenin 3 recruits cbp co activator to facilitate histone h3 h4 acetylation in the target gene insm1
FEBS Letters, 2007Co-Authors: Mary B. Breslin, Hong-wei Wang, Amy Pierce, Rebecca Aucoin, Michael S. LanAbstract:INSM1 is a downstream target gene of Neurogenin 3 (ngn3). A promoter construct containing the -426/+40bp region transiently co-transfected into NIH-3T3 cells with a ngn3 expression plasmid resulted in a 12-fold increase in promoter activity. The ngn3/E47 heterodimer selectively binds and activates the E-box3 of the INSM1 promoter. The endogenous ngn3 and CREB-binding protein (CBP) co-activator occupy the INSM1 promoter, resulting in hyper-acetylation of histone H3/H4 chromatin in a human neuroblastoma cell line, IMR-32. Additionally, adenoviral ngn3 can induce endogenous INSM-1 expression in pancreatic ductal carcinoma-1 cells through the recruitment of CBP to the INSM1 promoter and increase the acetylation of the INSM1 promoter region.
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Neurogenin 3 recruits CBP co-activator to facilitate histone H3/H4 acetylation in the target gene INSM1.
FEBS letters, 2007Co-Authors: Mary B. Breslin, Hong-wei Wang, Amy Pierce, Rebecca Aucoin, Michael S. LanAbstract:INSM1 is a downstream target gene of Neurogenin 3 (ngn3). A promoter construct containing the -426/+40bp region transiently co-transfected into NIH-3T3 cells with a ngn3 expression plasmid resulted in a 12-fold increase in promoter activity. The ngn3/E47 heterodimer selectively binds and activates the E-box3 of the INSM1 promoter. The endogenous ngn3 and CREB-binding protein (CBP) co-activator occupy the INSM1 promoter, resulting in hyper-acetylation of histone H3/H4 chromatin in a human neuroblastoma cell line, IMR-32. Additionally, adenoviral ngn3 can induce endogenous INSM-1 expression in pancreatic ductal carcinoma-1 cells through the recruitment of CBP to the INSM1 promoter and increase the acetylation of the INSM1 promoter region.
Andrew B Leiter - One of the best experts on this subject based on the ideXlab platform.
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basic helix loop helix transcription factors and enteroendocrine cell differentiation
Diabetes Obesity and Metabolism, 2011Co-Authors: Hui Joyce Li, B Johnston, N. K. Singh, Andrew B LeiterAbstract:For over thirty years it has been known that enteroendocrine cells derive from common precursor cells in the intestinal crypts. Until recently relatively little was understood about the events that result in commitment to endocrine differentiation or the eventual segregation of over 10 different hormone expressing cell types in the gastrointestinal tract. Enteroendocrine cells arise from pluripotent intestinal stem cells. Differentiation of enteroendocrine cells is controlled by the sequential expression of three basic helix loop helix transcription factors, Math1, Neurogenin 3, and NeuroD. Math1 expression is required for specification and segregation of the intestinal secretory lineage (Paneth, goblet, and enteroendocrine cells) from the absorptive enterocyte lineage. Neurogenin 3 represents the earliest stage of enteroendocrine differentiation and in its absence enteroendocrine cells fail to develop. Subsequent expression of NeuroD appears to represent a later stage of differentiation for maturing enteroendocrine cells. Enteroendocrine cell fate is inhibited by the Notch signaling pathway, which appears to inhibit both Math1 and Neurogenin 3. Understanding enteroendocrine cell differentiation will become increasingly important for identifying potential future targets for common diseases like diabetes and obesity.
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Differential requirements for Neurogenin 3 in the development of POMC and NPY neurons in the hypothalamus
Developmental biology, 2010Co-Authors: Michelle Pelling, Andrew B Leiter, Gérard Gradwohl, Neal Anthwal, David E. G. Mcnay, François Guillemot, Siew-lan AngAbstract:The neuroendocrine hypothalamus regulates a spectrum of essential biological processes and underlies a range of diseases from growth failure to obesity. While the exploration of hypothalamic function has progressed well, knowledge of hypothalamic development is poor. In particular, very little is known about the processes underlying the genesis and specification of the neurons in the arcuate and ventromedial nuclei. Recent studies demonstrate that the proneural basic helix-loop-helix transcription factor Mash1 is required for neurogenesis and neuronal subtype specification in the ventral hypothalamus. We demonstrate here that Ngn3, another basic helix-loop-helix transcription factor, is expressed in mitotic progenitors in the arcuate and ventromedial hypothalamic regions of mouse embryos from embryonic days 9.5-17.5. Genetic fate mapping and loss of function studies in mice demonstrate that Ngn3+ progenitors contribute to subsets of POMC, NPY, TH and SF1 neurons and is required for the specification of these neuronal subtypes in the ventral hypothalamus. Interestingly, while Ngn3 promotes the development of arcuate POMC and ventromedial SF1 neurons, it inhibits the development of NPY and TH neurons in the arcuate nuclei. Given the opposing roles of POMC and NPY neurons in regulating food intake, these results indicate that Ngn3 plays a central role in the generation of neuronal populations controlling energy homeostasis in mice.
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Neurogenin 3-Specific Dipeptidyl Peptidase-2 Deficiency Causes Impaired Glucose Tolerance, Insulin Resistance, and Visceral Obesity
Endocrinology, 2009Co-Authors: Olga V. Danilova, Andrew B Leiter, Albert K. Tai, Deanna A. Mele, Martin Beinborn, Andrew S. Greenberg, James W. Perfield, Jason Defuria, Praful S. Singru, Ronald M. LechanAbstract:The control of glucose metabolism is a complex process, and dysregulation at any level can cause impaired glucose tolerance and insulin resistance. These two defects are well-known characteristics associated with obesity and onset of type 2 diabetes. Here we introduce the N-terminal dipeptidase, DPP2, as a novel regulator of the glucose metabolism. We generated mice with a Neurogenin 3 (NGN3)-specific DPP2 knockdown (kd) to explore a possible role of DPP2 in maintaining metabolic homeostasis. These mice spontaneously developed hyperinsulinemia, glucose intolerance, and insulin resistance by 4 months of age. In addition, we observed an increase in food intake in DPP2 kd mice, which was associated with a significant increase in adipose tissue mass and enhanced liver steatosis but no difference in body weight. In accordance with these findings, the mutant mice had a higher rate of respiratory exchange than the control littermates. This phenotype was exacerbated with age and when challenged with a high-fat diet. We report, for the first time, that DPP2 enzyme activity is essential for preventing hyperinsulinemia and maintaining glucose homeostasis. Interestingly, the phenotype of NGN3-DPP2 kd mice is opposite that of DPP4 knockout mice with regard to glucose metabolism, namely the former have normal glucagon-like peptide 1 levels but present with glucose intolerance, whereas the latter have increased glucagon-like peptide 1, which is accompanied by augmented glucose tolerance.
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Enteroendocrine precursors differentiate independently of Wnt and form serotonin expressing adenomas in response to active β-catenin
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Yang Wang, Maryann Giel-moloney, Guido Rindi, Andrew B LeiterAbstract:Wnt signaling is required for the maintenance of intestinal stem cells and self-renewal of the intestinal epithelium. Intestinal cancers are frequently associated with mutations that activate the Wnt pathway. The role of Wnt signaling on differentiation of lineage-specific precursors in the intestine is not well characterized. Here, we show that specification of enteroendocrine but not Paneth cells occurs independently of Wnt signals by conditional deletion of β-catenin in immature cells expressing the transcription factor, Neurogenin 3. In addition, we determined whether Neurogenin 3-expressing cells respond to abnormal Wnt signaling. Activation of the Wnt pathway by conditionally deleting exon 3 of the β-catenin gene at an early stage of enteroendocrine cell differentiation induced small-intestinal adenomas expressing serotonin, a feature not previously described in other tumors induced by Wnt in mice. In contrast, excision of exon 3 of β-catenin at a later stage of enteroendocrine differentiation did not produce tumors. These results provide direct evidence that some intestinal lineages are specified independently of the Wnt pathway and may lead to a better understanding of the spectrum of neuroendocrine differentiation frequently seen in human gastrointestinal cancer.
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Neurogenin 3-expressing progenitor cells in the gastrointestinal tract differentiate into both endocrine and non-endocrine cell types
Developmental biology, 2004Co-Authors: Susan E. Schonhoff, Maryann Giel-moloney, Andrew B LeiterAbstract:Mice deficient for the transcription factor Neurogenin 3 (ngn3) fail to develop endocrine cells in the intestine and pancreas and show partial endocrine differentiation in the stomach. We expressed Cre recombinase under control of a ngn3 BAC to achieve high fidelity cell lineage tracing in vivo to determine whether endocrine cells in these organs differentiate from NGN3+ precursor cells. Our results indicate that all small intestinal enteroendocrine cells arise from ngn3-expressing cells and confirm that NGN3+ cells give rise to all pancreatic endocrine cells as noted previously. By examining mice at a developmental stage when all of the cell types in the stomach have differentiated, we have delineated region-associated differences in endocrine differentiation. A much smaller fraction of endocrine cells populating the acid-producing region of the stomach is derived from NGN3+ precursor in contrast to the antral-pyloric region. Unexpectedly, ngn3 is expressed in cells that adopt non-endocrine cell fates including significant fractions of goblet and Paneth cells in the intestine and a small number of duct and acinar cells in the pancreas. Rarely, ngn3 was expressed in pluripotent cells in intestinal crypts with resultant labeling of an entire crypt-villus unit. Thus, ngn3 expression occurs in mixed populations of immature cells that are not irreversibly committed to endocrine differentiation.
Isabel Ruiz-palmero - One of the best experts on this subject based on the ideXlab platform.
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Interaction of sex chromosome complement, gonadal hormones and neuronal steroid synthesis on the sexual differentiation of mammalian neurons.
Journal of neurogenetics, 2017Co-Authors: MarÃa J. Cambiasso, Isabel Ruiz-palmero, María Ángeles Arévalo, MarÃa J. Scerbo, Carla Daniela Cisternas, Iñigo Azcoitia, Luis-miguel Garcia-seguraAbstract:Female mouse hippocampal and hypothalamic neurons growing in vitro show a faster development of neurites than male mouse neurons. This sex difference in neuritogenesis is determined by higher expression levels of the neuritogenic factor Neurogenin 3 in female neurons. Experiments with the four core genotype mouse model, in which XX and XY animals with male gonads and XX and XY animals with female gonads are generated, indicate that higher levels of Neurogenin 3 in developing neurons are determined by the presence of the XX chromosome complement. Female XX neurons express higher levels of estrogen receptors than male XY neurons. In female XX neurons, neuronal derived estradiol increases Neurogenin 3 expression and neuritogenesis. In contrast, neuronal-derived estradiol is not able to upregulate Neurogenin 3 in male XY neurons, resulting in decreased neuritogenesis compared to female neurons. However, exogenous testosterone increases Neurogenin 3 expression and neuritogenesis in male XY neurons. These findings suggest that sex differences in neuronal development are determined by the interaction of sex chromosomes, neuronal derived estradiol and gonadal hormones.
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Oestradiol synthesized by female neurons generates sex differences in neuritogenesis
Scientific reports, 2016Co-Authors: Isabel Ruiz-palmero, Luis M. Garcia-segura, Ana Ortiz-rodriguez, Roberto C. Melcangi, Donatella Caruso, Gabriele M. Rune, María Ángeles ArévaloAbstract:Testosterone produced by the foetal testis is converted by male neurons to oestradiol, which masculinizes neuronal morphology. Female neurons are known to synthesize oestradiol in absence of exogenous testosterone. However, the role of neuronal oestradiol on the differentiation of foetal female neurons is unknown. Here we show that, due to endogenous neuronal oestradiol synthesis, female hippocampal neurons have higher expression of the neuritogenic protein Neurogenin 3 and enhanced neuritogenesis than males. Exogenous application of testosterone or its metabolite dihydrotestosterone increases Neurogenin 3 expression and promotes neuritogenesis in males, but reduces these parameters in females. Together our data indicate that gonadal-independent oestradiol synthesis by female neurons participates in the generation of sex differences in hippocampal neuronal development.
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A CRM1-mediated nuclear export signal is essential for cytoplasmic localization of Neurogenin 3 in neurons.
PloS one, 2013Co-Authors: Julia Simon-areces, Isabel Ruiz-palmero, Estefania Acaz-fonseca, Luis-miguel Garcia-segura, María Ángeles ArévaloAbstract:Neurogenin 3 (Ngn3), a proneural gene, regulates dendritogenesis and synaptogenesis in mouse hippocampal neurons. Ngn3 is transiently exported from the cell nucleus to the cytoplasm when neuronal polarity is initiated, suggesting that the nucleo-cytoplasmic transport of the protein is important for its action on neuronal development. In this study, we identified for the first time a functional nuclear export sequence (NES2; 131YIWALTQTLRIA142) in Ngn3. The green fluorescent protein (EGFP)-NES2 fusion protein was localized in the cytoplasm and its nucleo-cytoplasmic shuttling was blocked by the CRM1 specific export inhibitor leptomycin B. Mutation of a leucine residue to alanine (L135A) in the NES2 motif resulted in both cytoplasmic and nuclear localization of the EGFP-NES2 fusion protein and in the nuclear accumulation of ectopic full-length myc-Ngn3. In addition, point mutation of the leucine 135 counteracted the effects of Ngn3 on neuronal morphology and synaptic inputs indicating that the cytoplasmic localization of Ngn3 is important for neuronal development. Pharmacological perturbation of the cytoskeleton revealed that cytoplasmic Ngn3 is associated with microtubules.
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Estradiol Meets Notch Signaling in Developing Neurons
Frontiers in endocrinology, 2011Co-Authors: María Ángeles Arévalo, Isabel Ruiz-palmero, Julia Simon-areces, Estefania Acaz-fonseca, Iñigo Azcoitia, Luis M. Garcia-seguraAbstract:The transmembrane receptor Notch, a master developmental regulator, controls gliogenesis, neurogenesis and neurite development in the nervous system. Estradiol, acting as a hormonal signal or as a neurosteroid, also regulates these developmental processes. Here we review recent evidence indicating that estradiol and Notch signaling interact in developing hippocampal neurons by a mechanism involving the putative membrane receptor G protein-coupled receptor 30. This interaction is relevant for the control of neuronal differentiation, since the downregulation of Notch signaling by estradiol results in the upregulation of Neurogenin 3, which in turn promotes dendritogenesis.
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Notch/Neurogenin 3 Signalling is Involved in the Neuritogenic Actions of Oestradiol in Developing Hippocampal Neurones
Journal of neuroendocrinology, 2011Co-Authors: Isabel Ruiz-palmero, Julia Simon-areces, Luis M. Garcia-segura, María Ángeles ArévaloAbstract:The ovarian hormone oestradiol promotes neuritic outgrowth in different neuronal types, by mechanisms that remain elusive. Recent studies have shown that the Notch-regulated transcription factor Neurogenin 3 controls neuritogenesis. In the present study, we assessed whether oestradiol regulates Neurogenin 3 in primary hippocampal neurones. As expected, neuritogenesis was increased in the cultures treated with oestradiol. However, the neuritogenic action of oestradiol was not prevented by ICI 182,780, an antagonist of classical oestrogen receptors (ERs). Oestradiol decreased the expression of Hairy and Enhancer of Split-1, a Notch-regulated gene that negatively controls the expression on Neurogenin 3. Furthermore, oestradiol increased the expression of Neurogenin 3 and regulated its distribution between the neuronal cell nucleus and the cytoplasm. The effect of oestradiol on Neurogenin 3 expression was not blocked by antagonists of classical nuclear ER-mediated transcription and was not imitated by selective agonists of nuclear ERs. By contrast, G1, a ligand of G protein receptor 30/G protein-coupled ER, fully reproduced the effect of oestradiol on neuritogenesis, Neurogenin 3 expression and Neurogenin 3 subcellular localisation. Moreover, knockdown of Neurogenin 3 in neurones by transfection with small interference RNA for Neurogenin 3 completely abrogated the neuritogenic actions of oestradiol and G1. These results suggest that oestradiol regulates Neurogenin 3 in primary hippocampal neurones by a nonclassical steroid signalling mechanism, which involves the down-regulation of Notch activity and the activation of G protein receptor 30/G protein-coupled ER or of other unknown G1 targets. In addition, our findings indicate that Neurogenin 3 participates in the neuritogenic mechanisms of oestradiol in hippocampal neurones.
Luis M. Garcia-segura - One of the best experts on this subject based on the ideXlab platform.
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Oestradiol synthesized by female neurons generates sex differences in neuritogenesis
Scientific reports, 2016Co-Authors: Isabel Ruiz-palmero, Luis M. Garcia-segura, Ana Ortiz-rodriguez, Roberto C. Melcangi, Donatella Caruso, Gabriele M. Rune, María Ángeles ArévaloAbstract:Testosterone produced by the foetal testis is converted by male neurons to oestradiol, which masculinizes neuronal morphology. Female neurons are known to synthesize oestradiol in absence of exogenous testosterone. However, the role of neuronal oestradiol on the differentiation of foetal female neurons is unknown. Here we show that, due to endogenous neuronal oestradiol synthesis, female hippocampal neurons have higher expression of the neuritogenic protein Neurogenin 3 and enhanced neuritogenesis than males. Exogenous application of testosterone or its metabolite dihydrotestosterone increases Neurogenin 3 expression and promotes neuritogenesis in males, but reduces these parameters in females. Together our data indicate that gonadal-independent oestradiol synthesis by female neurons participates in the generation of sex differences in hippocampal neuronal development.
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Neurogenin 3 mediates sex chromosome effects on the generation of sex differences in hypothalamic neuronal development
Frontiers in cellular neuroscience, 2014Co-Authors: MarÃa J. Scerbo, Luis M. Garcia-segura, Alejandra Freire-regatillo, Carla Daniela Cisternas, Mabel Brunotto, M. Arévalo, MarÃa J. CambiassoAbstract:The organizational action of testosterone during critical periods of development is the cause of numerous sex differences in the brain. However, sex differences in neuritogenesis have been detected in primary neuronal hypothalamic cultures prepared before the peak of testosterone production by fetal testis. In the present study we assessed the hypothesis of that cell-autonomous action of sex chromosomes can differentially regulate the expression of the neuritogenic gene Neurogenin 3 (Ngn3) in male and female hypothalamic neurons, generating sex differences in neuronal development. Neuronal cultures were prepared from male and female E14 mouse hypothalami, before the fetal peak of testosterone. Female neurons showed enhanced neuritogenesis and higher expression of Ngn3 than male neurons. The silencing of Ngn3 abolished sex differences in neuritogenesis, decreasing the differentiation of female neurons. The sex difference in Ngn3 expression was determined by sex chromosomes, as demonstrated using the four core genotypes mouse model, in which a spontaneous deletion of the testis-determining gene Sry from the Y chromosome was combined with the insertion of the Sry gene onto an autosome. In addition, the expression of Ngn3, which is also known to mediate the neuritogenic actions of estradiol, was increased in the cultures treated with the hormone, but only in those from male embryos. Furthermore, the hormone reversed the sex differences in neuritogenesis promoting the differentiation of male neurons. These findings indicate that Ngn3 mediates both cell-autonomous actions of sex chromosomes and hormonal effects on neuritogenesis.
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Estradiol Meets Notch Signaling in Developing Neurons
Frontiers in endocrinology, 2011Co-Authors: María Ángeles Arévalo, Isabel Ruiz-palmero, Julia Simon-areces, Estefania Acaz-fonseca, Iñigo Azcoitia, Luis M. Garcia-seguraAbstract:The transmembrane receptor Notch, a master developmental regulator, controls gliogenesis, neurogenesis and neurite development in the nervous system. Estradiol, acting as a hormonal signal or as a neurosteroid, also regulates these developmental processes. Here we review recent evidence indicating that estradiol and Notch signaling interact in developing hippocampal neurons by a mechanism involving the putative membrane receptor G protein-coupled receptor 30. This interaction is relevant for the control of neuronal differentiation, since the downregulation of Notch signaling by estradiol results in the upregulation of Neurogenin 3, which in turn promotes dendritogenesis.
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Notch/Neurogenin 3 Signalling is Involved in the Neuritogenic Actions of Oestradiol in Developing Hippocampal Neurones
Journal of neuroendocrinology, 2011Co-Authors: Isabel Ruiz-palmero, Julia Simon-areces, Luis M. Garcia-segura, María Ángeles ArévaloAbstract:The ovarian hormone oestradiol promotes neuritic outgrowth in different neuronal types, by mechanisms that remain elusive. Recent studies have shown that the Notch-regulated transcription factor Neurogenin 3 controls neuritogenesis. In the present study, we assessed whether oestradiol regulates Neurogenin 3 in primary hippocampal neurones. As expected, neuritogenesis was increased in the cultures treated with oestradiol. However, the neuritogenic action of oestradiol was not prevented by ICI 182,780, an antagonist of classical oestrogen receptors (ERs). Oestradiol decreased the expression of Hairy and Enhancer of Split-1, a Notch-regulated gene that negatively controls the expression on Neurogenin 3. Furthermore, oestradiol increased the expression of Neurogenin 3 and regulated its distribution between the neuronal cell nucleus and the cytoplasm. The effect of oestradiol on Neurogenin 3 expression was not blocked by antagonists of classical nuclear ER-mediated transcription and was not imitated by selective agonists of nuclear ERs. By contrast, G1, a ligand of G protein receptor 30/G protein-coupled ER, fully reproduced the effect of oestradiol on neuritogenesis, Neurogenin 3 expression and Neurogenin 3 subcellular localisation. Moreover, knockdown of Neurogenin 3 in neurones by transfection with small interference RNA for Neurogenin 3 completely abrogated the neuritogenic actions of oestradiol and G1. These results suggest that oestradiol regulates Neurogenin 3 in primary hippocampal neurones by a nonclassical steroid signalling mechanism, which involves the down-regulation of Notch activity and the activation of G protein receptor 30/G protein-coupled ER or of other unknown G1 targets. In addition, our findings indicate that Neurogenin 3 participates in the neuritogenic mechanisms of oestradiol in hippocampal neurones.
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Neurogenin 3 cellular and subcellular localization in the developing and adult hippocampus
The Journal of comparative neurology, 2010Co-Authors: Julia Simon-areces, Luis M. Garcia-segura, Gema Membrive, Carmen Garcia-fernandez, María Ángeles ArévaloAbstract:Neurogenin 3 (Ngn3), a proneural gene controlled by the Notch receptor, is implicated in the control of dendrite morphology and synaptic plasticity of cultured hippocampal neurons. Here we report the localization and subcellular distribution of Ngn3 in the hippocampus in vivo and in neuronal cultures. In situ hybridization showed Ngn3 mRNA expression in the pyramidal layer and dentate gyrus of adult mouse hippocampus. Immunohistochemistry studies revealed that Ngn3 localization is mostly cytoplasmic in the hippocampal eminence at embryonic day (E)17 and postnatal day (P)0. At P10 it is cytoplasmic in CA1–CA3 pyramidal neurons and nuclear in granule cells of the dentate gyrus. In the adult hippocampus Ngn3 is localized in the nucleus and cytoplasm of both pyramidal neurons and granule cells. During development of cultured hippocampal neurons, Ngn3 mRNA expression is higher at stages of neuronal polarization, as judged by reverse-transcription polymerase chain reaction (RT-PCR), and it is mostly cytoplasmic. The tracking of the subcellular localization of Ngn3 in neurons infected with a virus expressing myc-Ngn3 suggests that the protein is quickly translocated to the cell nucleus after synthesis and then reexported to the cytoplasm. Treatment with leptomycinB, a potent and specific inhibitor of the exportin CRM1, induced its accumulation into the nucleus, suggesting that CRM1 mediates the nuclear export of Ngn3. These results suggest that Ngn3 may play a role in neuronal development by actions in the cytoplasm. J. Comp. Neurol. 518:1814–1824, 2010. © 2009 Wiley-Liss, Inc.