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Activation of adrenergic receptors affects cortical interneuron migration
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P.P. Kale, V. Addepalli / Int. J. Devl Neuroscience 30 (2012) 640–671
markers Oct4 and SSEA4. An upregulation of it was observed in the outgrowths obtained from these neurosphere like structures on adherent matrix. In the presence of the midbrain cues the DPSCs showed an upregulation of the dopaminergic cell specific transcription factors Nurr1 and En1. Immunofluorescence analysis showed that the induced cells were positive for mature neuronal marker Map2ab and dopaminergic cell type markers like tyrosine hydroxylase (TH), PitX3 and Nurr1. Flow cytometry data depicted that ∼63% of the induced DPSCs were positive for TH. Thus our preliminary data suggests that the neural crest derivative DPSCs have a predisposition towards neuronal lineage. DPSCs were not only capable of forming neurosphere like clusters in non-adherent condition and NSC media but could also respond to midbrain cues and undergo transdifferentiation. doi:10.1016/j.ijdevneu.2012.03.301
Cell-autonomous role of FGF receptors and Erk1/2 MAPK signaling in the regulation of myelination M. Furusho 1 , J.L. Dupree 2 , R. Bansal 1,∗ 1
Department of Neuroscience, University of Connecticut Medical School, Farmington, CT, USA 2 Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, USA
Despite intense research, signals that regulate myelin assembly and maintenance in the CNS are poorly understood. Here we investigated the cell-autonomous role of FGF-receptor (Fgfr) signaling via Fgfr1 and Fgfr2, in postnatal oligodendrocyte (OL) development and myelination. Conditional disruption of Fgfr1 and Fgfr2 (Fgfr1−/−; Fgfr2−/−) signaling did not affect OL progenitor proliferation or OL differentiation in vivo or in cultures of Fgfr1−/−; Fgfr2−/− spinal cord. Axon ensheathment and initiation of myelination were also unaffected. However, the rapid expansion of myelin sheath that normally occurs during the active phase of myelination and the slower increase during adulthood, did not occur in the Fgfr1−/−; Fgfr2−/− mice (myelin thickness remained largely unaltered from 15 postnatal days to 1 year). Lack of an increase in myelin thickness was also observed in single mutants of Fgfr1 or Fgfr2, but to a lesser extent than the double mutants, suggesting corporation of signaling between Fgfrs. In vitro, stimulation of FGF-receptors in mature OLs resulted in the expansion of their process network. This was abolished by pharmacological inhibition of Erk1/2 MAPK activity, suggesting the involvement of Erks in this process. Consistent with this, Erk1/2 MAPK activity was reduced in the hypomyelinated spinal cords of Fgfr1−/−; Fgfr2−/− mutants compared to controls. These data demonstrate the critical function of FGF-receptor signaling in OLs in the control of myelin sheath expansion, both during the rapid/active phase and the subsequent slower/gradual phase of myelination. Our study also suggests that Erk1/2 MAPKs are one of the potential downstream targets by which FGF receptors regulate the increase in myelin thickness. Supported by NIH grant NS38878 and NMSS, RG 4087-A-3. doi:10.1016/j.ijdevneu.2012.03.302
Activation of adrenergic receptors affects cortical interneuron migration O. Riccio 1,2 , S. Murthy 1,2,∗ , N. Hurni 1,2 , L. Hein 1,2,3 , A.G. Dayer 1,2 1
Department of Mental Health and Psychiatry, Geneva University Hospital, Switzerland 2 Department of Basic Neurosciences, University of Geneva, Switzerland 3 Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Germany E-mail address: [email protected] (S. Murthy). Among the external cues that control neuronal migration, monoamines such as serotonin and dopamine have been shown to modulate cortical interneuron migration. Noradrenaline is detected during late embryonic cortical development and adrenergic receptors are developmentally expressed in the embryonic developing cortex. Direct evidence for a functional role of the adrenergic system on neuronal migration is lacking. To the best of our knowledge, no studies have explored the effects of adrenergic stimulation on cortical interneuron migration. In this study we first investigated the expression pattern of adrenergic receptors in cortical interneurons and found that cortical interneurons expressed several adrenergic receptors. Using time-lapse recordings in cortical slices to directly monitor the effects of adrenergic receptor stimulation on interneuron migration, we observed that alpha2 receptor activation inhibits the migration of cortical interneurons in a concentration-dependent and reversible manner. Furthermore, we observed that following alpha2 activation the directionality of migrating interneurons was significantly modified, suggesting that alpha2 stimulation could modulate their responsiveness to guidance cues. These results support the general hypothesis that during embryonic development noradrenaline regulates cellular processes involved in the formation of cortical circuits. doi:10.1016/j.ijdevneu.2012.03.303
Maternal immune activation induces IL-6-dependent alterations in cytokine and gene expression profiles in the offspring E.Y. Hsiao ∗ , P.H. Patterson California Institute of Technology, Division of Biology, USA E-mail address: [email protected] (E.Y. Hsiao). Infection in pregnant women is associated with increased risk for autism and schizophrenia in the offspring. In a mouse model of this risk factor, activation of the maternal immune system sets in motion a cascade of molecular events that ultimately result in autism- and schizophrenia-related behaviors in offspring. The finding that interleukin-6 (IL-6) is a crucial mediator of these effects led us to examine the mechanism by which this cytokine influences fetal development in vivo. We find that maternal immune activation (MIA) with a viral mimic, synthetic double-stranded RNA (poly(I:C)), increases IL-6 mRNA as well as maternally derived IL-6 protein in the placenta. Maternal IL-6 activates JAK/STAT3 signaling in fetally derived placental spongiotrophoblast cells, reflecting the direct transfer of the MIA response from the mother to the developing embryo. These actions at the materno-fetal interface are associated with altered cytokine profiles directly in the fetal brain. Luminex data reveals elevated levels of fetal brain IL-6, IL4, IP-10, MIP-1a and VEGF. Importantly, these changes are absent in fetal brains from offspring of poly(I:C)-injected IL-6 knockout mothers, demonstrating that IL-6 action is required for the induction of pro-inflammatory cytokines in the fetal brain after MIA. MIA also induces IL-6 mRNA expression directly in the fetal brain and IL-
P.P. Kale, V. Addepalli / Int. J. Devl Neuroscience 30 (2012) 640–671
markers Oct4 and SSEA4. An upregulation of it was observed in the outgrowths obtained from these neurosphere like structures on adherent matrix. In the presence of the midbrain cues the DPSCs showed an upregulation of the dopaminergic cell specific transcription factors Nurr1 and En1. Immunofluorescence analysis showed that the induced cells were positive for mature neuronal marker Map2ab and dopaminergic cell type markers like tyrosine hydroxylase (TH), PitX3 and Nurr1. Flow cytometry data depicted that ∼63% of the induced DPSCs were positive for TH. Thus our preliminary data suggests that the neural crest derivative DPSCs have a predisposition towards neuronal lineage. DPSCs were not only capable of forming neurosphere like clusters in non-adherent condition and NSC media but could also respond to midbrain cues and undergo transdifferentiation. doi:10.1016/j.ijdevneu.2012.03.301
Cell-autonomous role of FGF receptors and Erk1/2 MAPK signaling in the regulation of myelination M. Furusho 1 , J.L. Dupree 2 , R. Bansal 1,∗ 1
Department of Neuroscience, University of Connecticut Medical School, Farmington, CT, USA 2 Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, USA
Despite intense research, signals that regulate myelin assembly and maintenance in the CNS are poorly understood. Here we investigated the cell-autonomous role of FGF-receptor (Fgfr) signaling via Fgfr1 and Fgfr2, in postnatal oligodendrocyte (OL) development and myelination. Conditional disruption of Fgfr1 and Fgfr2 (Fgfr1−/−; Fgfr2−/−) signaling did not affect OL progenitor proliferation or OL differentiation in vivo or in cultures of Fgfr1−/−; Fgfr2−/− spinal cord. Axon ensheathment and initiation of myelination were also unaffected. However, the rapid expansion of myelin sheath that normally occurs during the active phase of myelination and the slower increase during adulthood, did not occur in the Fgfr1−/−; Fgfr2−/− mice (myelin thickness remained largely unaltered from 15 postnatal days to 1 year). Lack of an increase in myelin thickness was also observed in single mutants of Fgfr1 or Fgfr2, but to a lesser extent than the double mutants, suggesting corporation of signaling between Fgfrs. In vitro, stimulation of FGF-receptors in mature OLs resulted in the expansion of their process network. This was abolished by pharmacological inhibition of Erk1/2 MAPK activity, suggesting the involvement of Erks in this process. Consistent with this, Erk1/2 MAPK activity was reduced in the hypomyelinated spinal cords of Fgfr1−/−; Fgfr2−/− mutants compared to controls. These data demonstrate the critical function of FGF-receptor signaling in OLs in the control of myelin sheath expansion, both during the rapid/active phase and the subsequent slower/gradual phase of myelination. Our study also suggests that Erk1/2 MAPKs are one of the potential downstream targets by which FGF receptors regulate the increase in myelin thickness. Supported by NIH grant NS38878 and NMSS, RG 4087-A-3. doi:10.1016/j.ijdevneu.2012.03.302
Activation of adrenergic receptors affects cortical interneuron migration O. Riccio 1,2 , S. Murthy 1,2,∗ , N. Hurni 1,2 , L. Hein 1,2,3 , A.G. Dayer 1,2 1
Department of Mental Health and Psychiatry, Geneva University Hospital, Switzerland 2 Department of Basic Neurosciences, University of Geneva, Switzerland 3 Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Germany E-mail address: [email protected] (S. Murthy). Among the external cues that control neuronal migration, monoamines such as serotonin and dopamine have been shown to modulate cortical interneuron migration. Noradrenaline is detected during late embryonic cortical development and adrenergic receptors are developmentally expressed in the embryonic developing cortex. Direct evidence for a functional role of the adrenergic system on neuronal migration is lacking. To the best of our knowledge, no studies have explored the effects of adrenergic stimulation on cortical interneuron migration. In this study we first investigated the expression pattern of adrenergic receptors in cortical interneurons and found that cortical interneurons expressed several adrenergic receptors. Using time-lapse recordings in cortical slices to directly monitor the effects of adrenergic receptor stimulation on interneuron migration, we observed that alpha2 receptor activation inhibits the migration of cortical interneurons in a concentration-dependent and reversible manner. Furthermore, we observed that following alpha2 activation the directionality of migrating interneurons was significantly modified, suggesting that alpha2 stimulation could modulate their responsiveness to guidance cues. These results support the general hypothesis that during embryonic development noradrenaline regulates cellular processes involved in the formation of cortical circuits. doi:10.1016/j.ijdevneu.2012.03.303
Maternal immune activation induces IL-6-dependent alterations in cytokine and gene expression profiles in the offspring E.Y. Hsiao ∗ , P.H. Patterson California Institute of Technology, Division of Biology, USA E-mail address: [email protected] (E.Y. Hsiao). Infection in pregnant women is associated with increased risk for autism and schizophrenia in the offspring. In a mouse model of this risk factor, activation of the maternal immune system sets in motion a cascade of molecular events that ultimately result in autism- and schizophrenia-related behaviors in offspring. The finding that interleukin-6 (IL-6) is a crucial mediator of these effects led us to examine the mechanism by which this cytokine influences fetal development in vivo. We find that maternal immune activation (MIA) with a viral mimic, synthetic double-stranded RNA (poly(I:C)), increases IL-6 mRNA as well as maternally derived IL-6 protein in the placenta. Maternal IL-6 activates JAK/STAT3 signaling in fetally derived placental spongiotrophoblast cells, reflecting the direct transfer of the MIA response from the mother to the developing embryo. These actions at the materno-fetal interface are associated with altered cytokine profiles directly in the fetal brain. Luminex data reveals elevated levels of fetal brain IL-6, IL4, IP-10, MIP-1a and VEGF. Importantly, these changes are absent in fetal brains from offspring of poly(I:C)-injected IL-6 knockout mothers, demonstrating that IL-6 action is required for the induction of pro-inflammatory cytokines in the fetal brain after MIA. MIA also induces IL-6 mRNA expression directly in the fetal brain and IL-