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Susan Wray - One of the best experts on this subject based on the ideXlab platform.
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Nasal Placode development gnrh neuronal migration and kallmann syndrome
Frontiers in Cell and Developmental Biology, 2019Co-Authors: Yufei Shan, Niteace C Whittington, Susan WrayAbstract:The development of Gonadotropin releasing hormone-1(GnRH) neurons is important for a functional reproduction system in vertebrates. Disruption of GnRH results in hypogonadism and if occompanied by anosmia is termed Kallmann Syndrome (KS). From their origin in the Nasal Placode, GnRH neurons migrate along the olfactory-derived vomeroNasal axons to the Nasal forebrain junction and then turn caudally into the developing forebrain. Although research on the origin of GnRH neurons, their migration and genes associated with KS have identified multiple factors which influence development of this system, several aspects still remain unclear. This review discusses development of the olfactory system, factors that regulate GnRH neuron formation and development of the olfactory system, migration of the GnRH neurons from the nose into the brain, and mutations in humans with KS that result from disruption of normal GnRH/olfactory systems development.
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Image_3_GPR37 Signaling Modulates Migration of Olfactory Ensheathing Cells and Gonadotropin Releasing Hormone Cells in Mice.JPEG
2019Co-Authors: Hassan Saadi, Yufei Shan, Daniela Marazziti, Susan WrayAbstract:Gonadotropin releasing hormone (GnRH) neurons, part of the hypothalamic-pituitary-gonadal axis, regulate reproduction. Prenatally, GnRH neurons migrate into the brain from the Nasal Placode along terminal nerve fibers, intermixed with olfactory sensory axons and olfactory ensheathing cells (OECs). An expression analysis from embryonic GnRH neurons identified the G protein-coupled receptor 37 (GPR37 or PAEL-r). GPR37 has been linked to (1) juvenile Parkinson’s disease in humans, (2) oligodendrocyte differentiation, and (3) Wnt/β-catenin signaling during neurogenesis. In this study, the role of GPR37 was investigated in the developing GnRH/olfactory system. PCR and immunocytochemistry confirmed expression of GPR37 in migrating GnRH neurons as well as in OECs. Inhibition of GPR37 signaling in Nasal explants attenuated GnRH neuronal migration and OEC movement. Examination of GPR37 deficient mice revealed a decrease in the olfactory bulb nerve layer and attenuated/delayed maturation and migration of GnRH neurons into the brain. These data demonstrate a developmental role for GPR37 signaling in neural migration.Significance StatementReproduction is controlled by gonadotrophin releasing hormone (GnRH) neurons located in the central nervous system. Embryonically, GnRH neurons originate in the Nasal/olfactory Placode and migrate into the brain on axonal tracks from cells in the vomeroNasal organ, intermixed with olfactory sensory axons and olfactory ensheathing cells (OECs). An expression analysis from embryonic GnRH neurons identified the G protein-coupled receptor 37. Here we show that inhibition of GPR37 signaling in Nasal explants and mutant mice attenuated GnRH neuronal migration. Signaling via GPR37 also perturbed OEC movement, resulting in a decrease in the olfactory bulb nerve layer in vivo. Together, these results identify a new role for GPR37 signaling during development – modulating cell migration.
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GPR37 Signaling Modulates Migration of Olfactory Ensheathing Cells and Gonadotropin Releasing Hormone Cells in Mice
Frontiers Media S.A., 2019Co-Authors: Hassan Saadi, Yufei Shan, Daniela Marazziti, Susan WrayAbstract:Gonadotropin releasing hormone (GnRH) neurons, part of the hypothalamic-pituitary-gonadal axis, regulate reproduction. Prenatally, GnRH neurons migrate into the brain from the Nasal Placode along terminal nerve fibers, intermixed with olfactory sensory axons and olfactory ensheathing cells (OECs). An expression analysis from embryonic GnRH neurons identified the G protein-coupled receptor 37 (GPR37 or PAEL-r). GPR37 has been linked to (1) juvenile Parkinson’s disease in humans, (2) oligodendrocyte differentiation, and (3) Wnt/β-catenin signaling during neurogenesis. In this study, the role of GPR37 was investigated in the developing GnRH/olfactory system. PCR and immunocytochemistry confirmed expression of GPR37 in migrating GnRH neurons as well as in OECs. Inhibition of GPR37 signaling in Nasal explants attenuated GnRH neuronal migration and OEC movement. Examination of GPR37 deficient mice revealed a decrease in the olfactory bulb nerve layer and attenuated/delayed maturation and migration of GnRH neurons into the brain. These data demonstrate a developmental role for GPR37 signaling in neural migration.Significance StatementReproduction is controlled by gonadotrophin releasing hormone (GnRH) neurons located in the central nervous system. Embryonically, GnRH neurons originate in the Nasal/olfactory Placode and migrate into the brain on axonal tracks from cells in the vomeroNasal organ, intermixed with olfactory sensory axons and olfactory ensheathing cells (OECs). An expression analysis from embryonic GnRH neurons identified the G protein-coupled receptor 37. Here we show that inhibition of GPR37 signaling in Nasal explants and mutant mice attenuated GnRH neuronal migration. Signaling via GPR37 also perturbed OEC movement, resulting in a decrease in the olfactory bulb nerve layer in vivo. Together, these results identify a new role for GPR37 signaling during development – modulating cell migration
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Image_1_Reelin Can Modulate Migration of Olfactory Ensheathing Cells and Gonadotropin Releasing Hormone Neurons via the Canonical Pathway.JPEG
2018Co-Authors: Leigh Dairaghi, Stephanie Constantin, Filippo Casoni, Paolo Giacobini, Hassan Saadi, Ellen Flannery, Aybike Saglam, Brian W. Howell, Susan WrayAbstract:One key signaling pathway known to influence neuronal migration involves the extracellular matrix protein Reelin. Typically, signaling of Reelin occurs via apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR), and the cytoplasmic adapter protein disabled 1 (Dab1). However, non-canonical Reelin signaling has been reported, though no receptors have yet been identified. Cariboni et al. (2005) indicated Dab1-independent Reelin signaling impacts gonadotropin releasing hormone-1 (GnRH) neuronal migration. GnRH cells are essential for reproduction. Prenatal migration of GnRH neurons from the Nasal Placode to the forebrain, juxtaposed to olfactory axons and olfactory ensheathing cells (OECs), has been well documented, and it is clear that alterations in migration of these cells can cause delayed or absent puberty. This study was initiated to delineate the non-canonical Reelin signaling pathways used by GnRH neurons. Chronic treatment of Nasal explants with CR-50, an antibody known to interfere with Reelin homopolymerization and Dab1 phosphorylation, decreased the distance GnRH neurons and OECs migrated. Normal migration of these two cell types was observed when Reelin was co-applied with CR-50. Immunocytochemistry was performed to determine if OECs might transduce Reelin signals via the canonical pathway, and subsequently indirectly altering GnRH neuronal migration. We show that in mouse: (1) both OECs and GnRH cells express ApoER2, VLDLR and Dab1, and (2) GnRH neurons and OECs show a normal distribution in the brain of two mutant reeler lines. These results indicate that the canonical Reelin pathway is present in GnRH neurons and OECs, but that Reelin is not essential for development of these two systems in vivo.
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gnrh anosmia and hypogonadotropic hypogonadism where are we
Frontiers in Neuroendocrinology, 2015Co-Authors: Paolo E. Forni, Susan WrayAbstract:Gonadotropin releasing hormone (GnRH) neurons originate the Nasal Placode and migrate into the brain during prenatal development. Once within the brain, these cells become integral components of the hypothalamic–pituitary–gonadal axis, essential for reproductive function. Disruption of this system causes hypogonadotropic hypogonadism (HH). HH associated with anosmia is clinically defined as Kallman syndrome (KS). Recent work examining the developing Nasal region has shed new light on cellular composition, cell interactions and molecular cues responsible for the development of this system in different species. This review discusses some developmental aspects, animal models and current advancements in our understanding of pathologies affecting GnRH. In addition we discuss how development of neural crest derivatives such as the glia of the olfactory system and craniofacial structures control GnRH development and reproductive function.
Phillip R. Kramer - One of the best experts on this subject based on the ideXlab platform.
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Dysregulation of Semaphorin7A/β1-integrin signaling leads to defective GnRH-1 cell migration, abnormal gonadal development and altered fertility
Human molecular genetics, 2011Co-Authors: Andrea Messina, Susan Wray, Phillip R. Kramer, Filippo Casoni, Nicoletta Ferraris, Gabriella Cagnoni, Duncan E. Donohue, Alwin A. Derijck, Youri Adolfs, Aldo FasoloAbstract:Reproduction in mammals is dependent on the function of specific neurons that secrete gonadotropin-releasing hormone-1 (GnRH-1). These neurons originate prenatally in the Nasal Placode and migrate into the forebrain along the olfactory–vomeroNasal nerves. Alterations in this migratory process lead to defective GnRH-1 secretion, resulting in heterogeneous genetic disorders such as idiopathic hypogonadotropic hypogonadism (IHH), and other reproductive diseases characterized by the reduction or failure of sexual competence. Combining mouse genetics with in vitro models, we demonstrate that Semaphorin 7A (Sema7A) is essential for the development of the GnRH-1 neuronal system. Loss of Sema7A signaling alters the migration of GnRH-1 neurons, resulting in significantly reduced numbers of these neurons in the adult brain as well as in reduced gonadal size and subfertility. We also show that GnRH-1 cells differentially express the Sema7 receptors β1-integrin and Plexin C1 as a function of their migratory stage, whereas the ligand is robustly expressed along developing olfactory/vomeroNasal fibers. Disruption of Sema7A function in vitro inhibits β1-integrin-mediated migration. Analysis of Plexin C1−/− mice did not reveal any difference in the migratory process of GnRH-1 neurons, indicating that Sema7A mainly signals through β1-integrin to regulate GnRH-1 cell motility. In conclusion, we have identified Sema7A as a gene implicated in the normal development of the GnRH-1 system in mice and as a genetic marker for the elucidation of some forms of GnRH-1 deficiency in humans.
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Dysregulation of Semaphorin7A/b1-integrin signaling leads to defective GnRH-1 cell migration, abnormal gonadal development and altered fertility
2011Co-Authors: Andrea Messina, Susan Wray, Phillip R. Kramer, Nicoletta Ferraris, Gabriella Cagnoni, Duncan E. Donohue, Alwin A. Derijck, Youri Adolfs, Aldo Fasolo, Ronald J. PasterkampAbstract:Reproduction in mammals is dependent on the function of specific neurons that secrete gonadotropin-releasing hormone-1 (GnRH-1). These neurons originate prenatally in the Nasal Placode and migrate into the forebrain along the olfactory–vomeroNasal nerves. Alterations in this migratory process lead to defective GnRH-1 secretion, resulting in heterogeneous genetic disorders such as idiopathic hypogonadotropic hypo-gonadism (IHH), and other reproductive diseases characterized by the reduction or failure of sexual compe-tence. Combining mouse genetics with in vitro models, we demonstrate that Semaphorin 7A (Sema7A) is essential for the development of the GnRH-1 neuronal system. Loss of Sema7A signaling alters the migration of GnRH-1 neurons, resulting in significantly reduced numbers of these neurons in the adult brain as well as in reduced gonadal size and subfertility. We also show that GnRH-1 cells differentially express the Sema7 receptors b1-integrin and Plexin C1 as a function of their migratory stage, whereas the ligand is robustly expressed along developing olfactory/vomeroNasal fibers. Disruption of Sema7A function in vitro inhibits b1-integrin-mediated migration. Analysis of Plexin C12/2 mice did not reveal any difference in the migratory process of GnRH-1 neurons, indicating that Sema7A mainly signals through b1-integrin to regulate GnRH-1 cell motility. In conclusion, we have identified Sema7A as a gene implicated in the normal development of th
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Midline Nasal tissue influences nestin expression in Nasal-Placode-derived luteinizing hormone-releasing hormone neurons during development.
Developmental biology, 2000Co-Authors: Phillip R. Kramer, Susan WrayAbstract:Neurons differentiating into the luteinizing hormone-releasing hormone (LHRH) neuroendocrine phenotype are derived from the Nasal Placode. Cells within the vomeroNasal organ anlage that turn on LHRH gene and peptide expression subsequently migrate into the forebrain where they influence reproductive function. The molecular and cellular cues regulating differentiation and migration of these cells are unknown. Discovery of developmental markers can indicate proteins directing or associated with differentiation. Analysis of such markers after manipulation of external cues can elucidate important extracellular differentiation signals. Embryonic LHRH neurons were examined in vivo for Mash-1 and nestin, two factors that delineate precursor populations in PNS and forebrain CNS cells. Nestin, but not Mash-1, was detected in early expressing LHRH cells in the vomeroNasal organ anlage. These results were duplicated in LHRH neurons maintained in vitro in Nasal explants. Such LHRH cells expressed nestin mRNA but not Mash-1 mRNA and were also negative for three other olfactory epithelial developmental transcription factors, Math4A, Math4C/neurogenin1, and NeuroD mRNA. Experimental manipulation of Nasal explants revealed dual expression of nestin protein and LHRH in cells proximal to the vomeroNasal organ anlage that was dependent upon midline cartilaginous/mesenchymal tissues. Prolonged nestin expression in LHRH cells after midline removal is consistent with Nasal midline tissues modulating differentiation of LHRH neurons from the Nasal Placode.
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Ectopic expression of luteinizing hormone-releasing hormone and peripherin in the respiratory epithelium of mice lacking transcription factor AP-2α
Mechanisms of Development, 2000Co-Authors: Phillip R. Kramer, G Guerrero, Ramachandran Krishnamurthy, Pamela J. Mitchell, Susan WrayAbstract:Abstract The vertebrate transcription factor activator protein-2 (AP-2 α ) is involved in craniofacial morphogenesis. In the Nasal Placode AP-2 α expression delineates presumptive respiratory epithelia from olfactory epithelia, with AP-2 α expression restricted to the anterior region of the respiratory epithelium (absent from the olfactory epithelium) at later stages. To address the role AP-2 α plays in differentiation of cell groups in the Nasal Placode, the spatiotemporal expression pattern of four markers normally associated with olfactory epithelial structures was analyzed in mice lacking AP-2 α . These markers were the intermediate filament protein peripherin, the neuropeptide luteinizing hormone-releasing hormone (LHRH), the neural cell adhesion molecule (NCAM) and the olfactory transcription factor Olf-1. Development of cells expressing these markers was similar in both genotypes until embryonic day 12.5 (E12.5), indicating that the main olfactory epithelium and olfactory pit formation was normal. At E13.5 in mutant mice, ectopic LHRH neurons and peripherin axons were detected in respiratory epithelial areas, areas devoid of Olf-1 and NCAM staining. Over the next few days, an increase in total Nasal LHRH neurons occurred. The increase in Nasal LHRH neurons could be accounted for by LHRH neurons arising and migrating out of respiratory epithelial regions on peripherin-positive fibers. These results indicate that AP-2 α is not essential for the separation of the olfactory and respiratory epithelium from the Nasal Placode and is consistent with AP-2 α preventing recapitulation of developmental programs within the respiratory epithelium that lead to expression of LHRH and peripherin phenotypes.
Filippo Casoni - One of the best experts on this subject based on the ideXlab platform.
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Image_1_Reelin Can Modulate Migration of Olfactory Ensheathing Cells and Gonadotropin Releasing Hormone Neurons via the Canonical Pathway.JPEG
2018Co-Authors: Leigh Dairaghi, Stephanie Constantin, Filippo Casoni, Paolo Giacobini, Hassan Saadi, Ellen Flannery, Aybike Saglam, Brian W. Howell, Susan WrayAbstract:One key signaling pathway known to influence neuronal migration involves the extracellular matrix protein Reelin. Typically, signaling of Reelin occurs via apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR), and the cytoplasmic adapter protein disabled 1 (Dab1). However, non-canonical Reelin signaling has been reported, though no receptors have yet been identified. Cariboni et al. (2005) indicated Dab1-independent Reelin signaling impacts gonadotropin releasing hormone-1 (GnRH) neuronal migration. GnRH cells are essential for reproduction. Prenatal migration of GnRH neurons from the Nasal Placode to the forebrain, juxtaposed to olfactory axons and olfactory ensheathing cells (OECs), has been well documented, and it is clear that alterations in migration of these cells can cause delayed or absent puberty. This study was initiated to delineate the non-canonical Reelin signaling pathways used by GnRH neurons. Chronic treatment of Nasal explants with CR-50, an antibody known to interfere with Reelin homopolymerization and Dab1 phosphorylation, decreased the distance GnRH neurons and OECs migrated. Normal migration of these two cell types was observed when Reelin was co-applied with CR-50. Immunocytochemistry was performed to determine if OECs might transduce Reelin signals via the canonical pathway, and subsequently indirectly altering GnRH neuronal migration. We show that in mouse: (1) both OECs and GnRH cells express ApoER2, VLDLR and Dab1, and (2) GnRH neurons and OECs show a normal distribution in the brain of two mutant reeler lines. These results indicate that the canonical Reelin pathway is present in GnRH neurons and OECs, but that Reelin is not essential for development of these two systems in vivo.
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Reelin Can Modulate Migration of Olfactory Ensheathing Cells and Gonadotropin Releasing Hormone Neurons via the Canonical Pathway
Frontiers Media S.A., 2018Co-Authors: Leigh Dairaghi, Stephanie Constantin, Filippo Casoni, Paolo Giacobini, Hassan Saadi, Ellen Flannery, Aybike SaglamAbstract:One key signaling pathway known to influence neuronal migration involves the extracellular matrix protein Reelin. Typically, signaling of Reelin occurs via apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR), and the cytoplasmic adapter protein disabled 1 (Dab1). However, non-canonical Reelin signaling has been reported, though no receptors have yet been identified. Cariboni et al. (2005) indicated Dab1-independent Reelin signaling impacts gonadotropin releasing hormone-1 (GnRH) neuronal migration. GnRH cells are essential for reproduction. Prenatal migration of GnRH neurons from the Nasal Placode to the forebrain, juxtaposed to olfactory axons and olfactory ensheathing cells (OECs), has been well documented, and it is clear that alterations in migration of these cells can cause delayed or absent puberty. This study was initiated to delineate the non-canonical Reelin signaling pathways used by GnRH neurons. Chronic treatment of Nasal explants with CR-50, an antibody known to interfere with Reelin homopolymerization and Dab1 phosphorylation, decreased the distance GnRH neurons and OECs migrated. Normal migration of these two cell types was observed when Reelin was co-applied with CR-50. Immunocytochemistry was performed to determine if OECs might transduce Reelin signals via the canonical pathway, and subsequently indirectly altering GnRH neuronal migration. We show that in mouse: (1) both OECs and GnRH cells express ApoER2, VLDLR and Dab1, and (2) GnRH neurons and OECs show a normal distribution in the brain of two mutant reeler lines. These results indicate that the canonical Reelin pathway is present in GnRH neurons and OECs, but that Reelin is not essential for development of these two systems in vivo
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Suppression of β1-Integrin in Gonadotropin-Releasing Hormone Cells Disrupts Migration and Axonal Extension Resulting in Severe Reproductive Alterations
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012Co-Authors: Jyoti Parkash, Susan Wray, Filippo Casoni, Irene Cimino, Nicoletta Ferraris, Hélène Cappy, Vincent Prevot, Paolo GiacobiniAbstract:Reproduction in mammals is dependent on the function of hypothalamic neurons whose axons project to the hypothalamic median eminence (ME) where they release gonadotropin-releasing hormone (GnRH) into a specialized capillary network for delivery to the anterior pituitary. These neurons originate prenatally in the Nasal Placode and migrate into the forebrain along the olfactory-vomeroNasal nerves. The complex developmental events leading to the correct establishment of the GnRH system are tightly regulated by the specific spatiotemporal expression patterns of guidance cues and extracellular matrix molecules, the functions of which, in part, are mediated by their binding to β1-subunit-containing integrins. To determine the biological role of these cell-surface proteins in reproduction, Cre/LoxP technology was used to generate GnRH neuron-specific β1-integrin conditional KO (GnRH-Itgb1(-/-)) mice. Loss of β1-integrin signaling impaired migration of GnRH neurons, their axonal extension to the ME, timing of pubertal onset, and fertility in these mice. These results identify β1-integrin as a gene involved in normal development of the GnRH system and demonstrate a fundamental role for this protein in acquisition of normal reproductive competence in female mice.
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SDF and GABA interact to regulate axophilic migration of GnRH neurons.
Journal of cell science, 2012Co-Authors: Filippo Casoni, Michele Fornaro, B Ian Hutchins, Duncan Donohue, Brian G Condie, Susan WrayAbstract:Stromal derived growth factor (SDF-1) and gamma-aminobutyric acid (GABA) are two extracellular cues that regulate the rate of neuronal migration during development and may act synergistically. The molecular mechanisms of this interaction are still unclear. Gonadotropin releasing hormone-1 (GnRH) neurons are essential for vertebrate reproduction. During development, these neurons emerge from the Nasal Placode and migrate through the cribriform plate into the brain. Both SDF-1 and GABA have been shown to regulate the rate of GnRH neuronal migration by accelerating and slowing migration, respectively. As such, this system was used to explore the mechanism by which these molecules act to produce coordinated cell movement during development. In the present study, GABA and SDF-1 are shown to exert opposite effects on the speed of cell movement by activating depolarizing or hyperpolarizing signaling pathways, GABA via changes in chloride and SDF-1 via changes in potassium. GABA and SDF-1 were also found to act synergistically to promote linear rather than random movement. The simultaneous activation of these signaling pathways, therefore, results in tight control of cellular speed and improved directionality along the migratory pathway of GnRH neurons.
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Dysregulation of Semaphorin7A/β1-integrin signaling leads to defective GnRH-1 cell migration, abnormal gonadal development and altered fertility
Human molecular genetics, 2011Co-Authors: Andrea Messina, Susan Wray, Phillip R. Kramer, Filippo Casoni, Nicoletta Ferraris, Gabriella Cagnoni, Duncan E. Donohue, Alwin A. Derijck, Youri Adolfs, Aldo FasoloAbstract:Reproduction in mammals is dependent on the function of specific neurons that secrete gonadotropin-releasing hormone-1 (GnRH-1). These neurons originate prenatally in the Nasal Placode and migrate into the forebrain along the olfactory–vomeroNasal nerves. Alterations in this migratory process lead to defective GnRH-1 secretion, resulting in heterogeneous genetic disorders such as idiopathic hypogonadotropic hypogonadism (IHH), and other reproductive diseases characterized by the reduction or failure of sexual competence. Combining mouse genetics with in vitro models, we demonstrate that Semaphorin 7A (Sema7A) is essential for the development of the GnRH-1 neuronal system. Loss of Sema7A signaling alters the migration of GnRH-1 neurons, resulting in significantly reduced numbers of these neurons in the adult brain as well as in reduced gonadal size and subfertility. We also show that GnRH-1 cells differentially express the Sema7 receptors β1-integrin and Plexin C1 as a function of their migratory stage, whereas the ligand is robustly expressed along developing olfactory/vomeroNasal fibers. Disruption of Sema7A function in vitro inhibits β1-integrin-mediated migration. Analysis of Plexin C1−/− mice did not reveal any difference in the migratory process of GnRH-1 neurons, indicating that Sema7A mainly signals through β1-integrin to regulate GnRH-1 cell motility. In conclusion, we have identified Sema7A as a gene implicated in the normal development of the GnRH-1 system in mice and as a genetic marker for the elucidation of some forms of GnRH-1 deficiency in humans.
Anna Cariboni - One of the best experts on this subject based on the ideXlab platform.
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The role of semaphorin signaling in the etiology of hypogonadotropic hypogonadism.
Minerva endocrinologica, 2016Co-Authors: A. Lettieri, R. Oleari, Jessica Gimmelli, Valentina Andre, Anna CariboniAbstract:In mammals fertility depends on timely onset and cyclic secretion of gonadotropin-releasing hormone (GnRH), secreted by scattered hypothalamic neurons (GnRH neurons). These cells originate in the Nasal Placode and migrate first in the Nasal compartment, then through the cribriform plate and finally across the basal forebrain, before they set in their final position in the hypothalamus. This long journey is regulated by many different factors that could be mutated in neuroendocrine syndromes such as congenital hypogonadotropic hypogonadism (CHH), Kallmann Syndrome (KS) and CHARGE syndrome. Recently, semaphorins, a large family of molecules, previously discovered as axon guidance cues, are emerging as key regulators of the neuroendocrine control of GnRH neurons and are acquiring an increasing role in the etiopathogenesis of CHH and KS. Specifically, semaphorins play a multifaceted action in GnRH neuron biology: on one hand regulating their migration and survival during embryonic development and, on the other, controlling the plasticity of the median eminence (ME) in terms of its response to varying sex steroid hormone levels. In this review we will focus our attention on recent studies describing the roles of different semaphorins in the normal and pathological biology of the GnRH neuronal system.
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The molecular control of GnRH neuron development.
SpringerPlus, 2015Co-Authors: Anna Cariboni, Andre´ Valentina, Kathryn C. Davidson, John G. ParnavelasAbstract:Fertility critically depends by a small number of hypothalamic neurons secreting the neurohormone GnRH. During development GnRH neurons migrate from the Nasal Placode to the hypothalamus by following the migratory path formed by the vomeroNasal axons. Developmental defects of this process can cause congenital GnRH deficiency (GD), characterized by absent/delayed puberty and consequent infertility. The underlying mutated loci are for the majority of GD cases unknown, partially because of a poor understanding of the molecular mechanisms that control the development of these crucial neuroendocrine cells. Here we provide evidence of the importance of class 3 semaphorins and their receptors in this process. Specifically, I will explain how two different semaphorins play distinct roles during the migration of GnRH neurons. Thus, semaphorin3A affects the migration of GnRH neurons in the Nasal compartment, via the co-receptors Neuropilin-1 and 2, whereas semaphorin3E via its receptor plexind1 controls the survival of GnRH neurons once positioned in the hypothalamus. Accordingly, disrupted semaphorin signalling may be involved in the aethiopathogenesis of genetic diseases characterized by GnRH deficiency.
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CXC chemokine receptor 7 (CXCR7) affects the migration of GnRH neurons by regulating CXCL12 availability.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013Co-Authors: Fani Memi, Anna Cariboni, John G. Parnavelas, Philipp Abe, Fabienne Mackay, Ralf StummAbstract:Gonadotropin-releasing hormone (GnRH) neurons are neuroendocrine cells, located in the hypothalamus, that play an essential role in mammalian reproduction. These neurons originate in the Nasal Placode and migrate during embryonic development, in association with olfactory/vomeroNasal nerves, first in the nose, then through the cribriform plate to enter the forebrain, before settling in the hypothalamus. One of the molecules required for their early migration in the nose is the chemokine CXCL12, which is expressed in the embryonic Nasal mesenchyme in an increasing ventral to dorsal gradient, presumably guiding GnRH neurons toward the forebrain. Mice lacking CXCR4, the receptor for CXCL12, exhibit defective GnRH cell movement and a significant reduction in their number, suggesting that CXCL12/CXCR4 signaling is important in the migration and survival of these neurons. Here, we investigated the role of the more recently identified second CXCL12 receptor, CXCR7, in GnRH neuron development. We demonstrate that CXCR7 is expressed along the migratory path of GnRH neurons in the Nasal cavity and, although not expressed by GnRH neurons, it affects their migration as indicated by the ectopic accumulation of these cells in the Nasal compartment in CXCR7−/− mice. Absence of CXCR7 caused abnormal accumulation of CXCL12-RFP at CXCR4-positive sites in the Nasal area of CXCL12-RFP-transgenic mice and excessive CXCL12-dependent intracellular clustering of CXCR4 in GnRH neurons, suggesting internalization. These findings imply that CXCR7 regulates CXCL12 availability by acting as a scavenger along the migratory path of GnRH neurons and, thus, influences the migration of these cells in a noncell-autonomous manner.
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Slit2 and Robo3 modulate the migration of GnRH-secreting neurons
Development (Cambridge England), 2012Co-Authors: Anna Cariboni, William D. Andrews, Fani Memi, Athena R. Ypsilanti, Pavol Zelina, Alain Chédotal, John G. ParnavelasAbstract:Gonadotropin-releasing hormone (GnRH) neurons are born in the Nasal Placode and migrate along olfactory and vomeroNasal axons to reach the forebrain and settle in the hypothalamus, where they control reproduction. The molecular cues that guide their migration have not been fully identified, but are thought to control either cell movement directly or the patterning of their axonal substrates. Using genetically altered mouse models we show that the migration of GnRH neurons is directly modulated by Slit2 and Robo3, members of the axon guidance Slit ligand and Robo receptor families. Mice lacking Slit2 or Robo3 have a reduced number of GnRH neurons in the forebrain, but a normal complement of their supporting axons, pointing to a direct role for these molecules in GnRH neuron migration.
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From nose to fertility: the long migratory journey of gonadotropin-releasing hormone neurons.
Trends in neurosciences, 2007Co-Authors: Anna Cariboni, Roberto Maggi, John G. ParnavelasAbstract:Gonadotropin-releasing hormone (GnRH) neurons, a small number of cells dispersed in the hypothalamic region of the basal forebrain, play an important role in reproductive function. These neurons originate in the Nasal Placode and migrate, first in the Nasal compartment, then through the cribriform plate and finally through the basal forebrain, before they attain their positions in the hypothalamus. Their movement through changing molecular environments suggests that numerous factors are involved in different phases of their migration. In humans, failure of GnRH neurons to migrate normally results in delayed or absent pubertal maturation and infertility. Advances in genetic and molecular biologic techniques in this decade have allowed us to gain insights into several molecules that affect the migration of GnRH neurons and, consequently, play a role in the establishment and maintenance of reproductive function.
John G. Parnavelas - One of the best experts on this subject based on the ideXlab platform.
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The molecular control of GnRH neuron development.
SpringerPlus, 2015Co-Authors: Anna Cariboni, Andre´ Valentina, Kathryn C. Davidson, John G. ParnavelasAbstract:Fertility critically depends by a small number of hypothalamic neurons secreting the neurohormone GnRH. During development GnRH neurons migrate from the Nasal Placode to the hypothalamus by following the migratory path formed by the vomeroNasal axons. Developmental defects of this process can cause congenital GnRH deficiency (GD), characterized by absent/delayed puberty and consequent infertility. The underlying mutated loci are for the majority of GD cases unknown, partially because of a poor understanding of the molecular mechanisms that control the development of these crucial neuroendocrine cells. Here we provide evidence of the importance of class 3 semaphorins and their receptors in this process. Specifically, I will explain how two different semaphorins play distinct roles during the migration of GnRH neurons. Thus, semaphorin3A affects the migration of GnRH neurons in the Nasal compartment, via the co-receptors Neuropilin-1 and 2, whereas semaphorin3E via its receptor plexind1 controls the survival of GnRH neurons once positioned in the hypothalamus. Accordingly, disrupted semaphorin signalling may be involved in the aethiopathogenesis of genetic diseases characterized by GnRH deficiency.
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CXC chemokine receptor 7 (CXCR7) affects the migration of GnRH neurons by regulating CXCL12 availability.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013Co-Authors: Fani Memi, Anna Cariboni, John G. Parnavelas, Philipp Abe, Fabienne Mackay, Ralf StummAbstract:Gonadotropin-releasing hormone (GnRH) neurons are neuroendocrine cells, located in the hypothalamus, that play an essential role in mammalian reproduction. These neurons originate in the Nasal Placode and migrate during embryonic development, in association with olfactory/vomeroNasal nerves, first in the nose, then through the cribriform plate to enter the forebrain, before settling in the hypothalamus. One of the molecules required for their early migration in the nose is the chemokine CXCL12, which is expressed in the embryonic Nasal mesenchyme in an increasing ventral to dorsal gradient, presumably guiding GnRH neurons toward the forebrain. Mice lacking CXCR4, the receptor for CXCL12, exhibit defective GnRH cell movement and a significant reduction in their number, suggesting that CXCL12/CXCR4 signaling is important in the migration and survival of these neurons. Here, we investigated the role of the more recently identified second CXCL12 receptor, CXCR7, in GnRH neuron development. We demonstrate that CXCR7 is expressed along the migratory path of GnRH neurons in the Nasal cavity and, although not expressed by GnRH neurons, it affects their migration as indicated by the ectopic accumulation of these cells in the Nasal compartment in CXCR7−/− mice. Absence of CXCR7 caused abnormal accumulation of CXCL12-RFP at CXCR4-positive sites in the Nasal area of CXCL12-RFP-transgenic mice and excessive CXCL12-dependent intracellular clustering of CXCR4 in GnRH neurons, suggesting internalization. These findings imply that CXCR7 regulates CXCL12 availability by acting as a scavenger along the migratory path of GnRH neurons and, thus, influences the migration of these cells in a noncell-autonomous manner.
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Slit2 and Robo3 modulate the migration of GnRH-secreting neurons
Development (Cambridge England), 2012Co-Authors: Anna Cariboni, William D. Andrews, Fani Memi, Athena R. Ypsilanti, Pavol Zelina, Alain Chédotal, John G. ParnavelasAbstract:Gonadotropin-releasing hormone (GnRH) neurons are born in the Nasal Placode and migrate along olfactory and vomeroNasal axons to reach the forebrain and settle in the hypothalamus, where they control reproduction. The molecular cues that guide their migration have not been fully identified, but are thought to control either cell movement directly or the patterning of their axonal substrates. Using genetically altered mouse models we show that the migration of GnRH neurons is directly modulated by Slit2 and Robo3, members of the axon guidance Slit ligand and Robo receptor families. Mice lacking Slit2 or Robo3 have a reduced number of GnRH neurons in the forebrain, but a normal complement of their supporting axons, pointing to a direct role for these molecules in GnRH neuron migration.
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From nose to fertility: the long migratory journey of gonadotropin-releasing hormone neurons.
Trends in neurosciences, 2007Co-Authors: Anna Cariboni, Roberto Maggi, John G. ParnavelasAbstract:Gonadotropin-releasing hormone (GnRH) neurons, a small number of cells dispersed in the hypothalamic region of the basal forebrain, play an important role in reproductive function. These neurons originate in the Nasal Placode and migrate, first in the Nasal compartment, then through the cribriform plate and finally through the basal forebrain, before they attain their positions in the hypothalamus. Their movement through changing molecular environments suggests that numerous factors are involved in different phases of their migration. In humans, failure of GnRH neurons to migrate normally results in delayed or absent pubertal maturation and infertility. Advances in genetic and molecular biologic techniques in this decade have allowed us to gain insights into several molecules that affect the migration of GnRH neurons and, consequently, play a role in the establishment and maintenance of reproductive function.
