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Development of respiratory rhythm generating circuits in the mouse embryo hindbrain
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Symposium Abstracts ISDN 2012 / Int. J. Devl Neuroscience 30 (2012) 626–639
ISDN2012 0270 Development of respiratory rhythm generating circuits in the mouse embryo hindbrain Gilles Fortin Neurobiologie & Developpement, CNRS UPR3294, Inst. de Neurobiol. Alfred Fessard, Gif-sur-Yvette, France We breathe roughly half a billion times in a lifetime, generally in an effortless and even unconscious manner owing to activity of a respiratory central pattern generator (CPG) located in the hindbrain. The respiratory CPG relies on the coupling of two prominent rhythmogenic sites located in the medulla, the pre-Bötzinger Complex (preBötC) and the para-Facial Respiratory Group (pFRG). Working in the mouse embryo, we have identified the emergence of forerunning versions of these two oscillators using developmental genetics tools, electrophysiological and optical recordings. We have defined molecular and functional signatures for cells composing each oscillator. More precisely, data will be presented showing the independent developments of (i) an Egr2- (also known as Krox20) derived, Phox2b/Lbx1/Atoh1-expressing embryonic parafacial oscillator and (ii) a Dbx1-derived populations of glutamatergic interneurons required for both preBötC rhythm generation and bilateral synchrony through Robo3-dependent axonal commissural pathfinding. These results indicate that each oscillator is not assembled from cells of disparate origins. Rather, each oscillator is made of cells with selective built-in functional properties that derive from a discrete transcriptionally defined domain of the neuroepithelium. Hence, the dual organisation of the respiratory CPG seems to reflect the modular origin of its composing cells. Work supported by CNRS, INSERM, ANR grants to GF. http://dx.doi.org/10.1016/j.ijdevneu.2012.10.092 ISDN2012 0271 The role of genetic programs and activity in the development of cortical interneuron diversity Gord Fishell, Natalia De Marco, Theofanis Karayannis, Renata Batista-Brito, Jennifer Close, Xavier Jaglin, Goichi Miyoshi NYU Neuroscience Institute, NYU Langone Medical Center, NY, USA A key feature of the central nervous system is its ability to process multimodal sensory information. The ensembles of neurons that permit the performance of such a challenging task are established during development. In the somatosensory cortex, GABAergic interneurons born in the ventral telencephalon undergo protracted migration to reach their final postion in the cortex and acquire stereotypic morphologies before contacting their targets, the pyramidal cells and other interneurons. However, the cellular and molecular mechanisms that regulate interneuron maturation are poorly understood. In my talk, I will discuss the mechanisms by which gene expression and neuronal activity regulate the establishment of cortical interneuron subtypes, as well as their requisite laminar targeting and morphology. These questions will be examined through a combination of mouse genetics and physiology. The development of cortical interneuron diversity appears to arise through two sequential steps. We hypothesize that the initial specification of interneurons occurs at the progenitor stage and utilizes intrinsic genetic programs to divide them into approximately seven “cardinal” groups. Upon becoming postmitotic, immature interneurons migrate and integrate within distinct cortical regions. As they integrate into cortical plate, we have recently demonstrated that activity is selectively required for their selection of cortical laminae and morphological maturation. We suspect they are also receiving further signals that aid in their appropriate regional differentia-
tion. Our hope is that through these approaches the cellular logic underlying circuit maturation can be understood and provide a systematic approach for the visualization and targetted manipulation of interneuron excitability. As we believe that dysfunction of cortical interneurons underlies a variety of affective neurological disorders, our approach provides the means to explore the etiology of brain pathology. http://dx.doi.org/10.1016/j.ijdevneu.2012.10.093 ISDN2012 0272 Tortillas and toxins: Gene–environment fumonisin-induced neural tube defects
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J. Gelineau-van Waes 1 , J. Maddox 1 , M. Rainey 1 , N. Gardner 1 , A. Sachs 1 , K. Voss 2 , R.T. Riley 2 1 Dept. of Pharmacology, Creighton University School of Medicine, Omaha, NE, United States 2 Toxicology and Mycotoxin Research Unit, USDA-ARS, Athens, GA, United States Fumonisin B1 (FB1) is a mycotoxin produced by a common fungal contaminant of maize. In populations that rely heavily on maize as a dietary staple, consumption of FB1-contaminated food during early pregnancy has been associated with increased risk for neural tube defects (NTDs). Administration of FB1 to pregnant LM/Bc mice causes exencephaly in 79% of exposed embryos. FB1 inhibits the enzyme ceramide synthase in de novo sphingolipid biosynthesis, resulting in decreased formation of ceramide and increased accumulation of sphinganine and its phosphorylated metabolite sphinganine-1-phosphate (Sa1P). Sa1P is a bioactive lipid mediator that functions as a ligand for a family of G protein-coupled ‘sphingosine-1-phosphate’ (S1P) receptors. Sa1P is significantly elevated in maternal blood spots, placenta, and amniotic fluid of LM/Bc mice after FB1 administration. Increased levels of Sa1P are also observed in cultured mouse neural progenitor cells treated with FB1. FTY720 is phosphorylated in vivo to form FTY720-P, which in turn functions as an S1P receptor agonist. Administration of FTY720 to pregnant SWV and LM/Bc mice causes 40–60% NTDs in exposed offspring, implicating a role for S1P receptor-mediated signaling in both FB1 and FTY720-induced NTDs. Lass1 is the gene that codes for the predominant isoform of ceramide synthase expressed in neural tissue. The Lass1 transcript is bicistronic with Gdf1 (growth differentiation factor 1), a member of the TGF superfamily. Inactivation of Gdf1 in knockout mice leads to increased expression of the remaining Lass1 portion of the Lass1–Gdf1 transcript. Conversely, FB1 inhibition of LASS1 results in increased Gdf1 expression in the open neural folds of exencephalic LM/Bc embryos, suggesting reciprocal feedback between Lass1 and Gdf1. Models for cross-talk between S1P receptor and TGF signaling pathways have been proposed. Cross-talk between Sa1P activation of S1P receptors and GDF1/Nodal/Activin signaling may be involved in the failure of neural tube closure after exposure to FB1.
http://dx.doi.org/10.1016/j.ijdevneu.2012.10.094 ISDN2012 0273 Phox2b and the viscero-somatic duality of the medulla Jean-Franc¸ois Brunet Institut de Biologie de l’École normale supérieure, ENS, 46 rue d’Ulm, 75005 Paris, France Taste and most sensory inputs required for the feedback regulation of digestive, respiratory and cardiovascular organs are conveyed to the central nervous system by so-called “visceral”
Symposium Abstracts ISDN 2012 / Int. J. Devl Neuroscience 30 (2012) 626–639
ISDN2012 0270 Development of respiratory rhythm generating circuits in the mouse embryo hindbrain Gilles Fortin Neurobiologie & Developpement, CNRS UPR3294, Inst. de Neurobiol. Alfred Fessard, Gif-sur-Yvette, France We breathe roughly half a billion times in a lifetime, generally in an effortless and even unconscious manner owing to activity of a respiratory central pattern generator (CPG) located in the hindbrain. The respiratory CPG relies on the coupling of two prominent rhythmogenic sites located in the medulla, the pre-Bötzinger Complex (preBötC) and the para-Facial Respiratory Group (pFRG). Working in the mouse embryo, we have identified the emergence of forerunning versions of these two oscillators using developmental genetics tools, electrophysiological and optical recordings. We have defined molecular and functional signatures for cells composing each oscillator. More precisely, data will be presented showing the independent developments of (i) an Egr2- (also known as Krox20) derived, Phox2b/Lbx1/Atoh1-expressing embryonic parafacial oscillator and (ii) a Dbx1-derived populations of glutamatergic interneurons required for both preBötC rhythm generation and bilateral synchrony through Robo3-dependent axonal commissural pathfinding. These results indicate that each oscillator is not assembled from cells of disparate origins. Rather, each oscillator is made of cells with selective built-in functional properties that derive from a discrete transcriptionally defined domain of the neuroepithelium. Hence, the dual organisation of the respiratory CPG seems to reflect the modular origin of its composing cells. Work supported by CNRS, INSERM, ANR grants to GF. http://dx.doi.org/10.1016/j.ijdevneu.2012.10.092 ISDN2012 0271 The role of genetic programs and activity in the development of cortical interneuron diversity Gord Fishell, Natalia De Marco, Theofanis Karayannis, Renata Batista-Brito, Jennifer Close, Xavier Jaglin, Goichi Miyoshi NYU Neuroscience Institute, NYU Langone Medical Center, NY, USA A key feature of the central nervous system is its ability to process multimodal sensory information. The ensembles of neurons that permit the performance of such a challenging task are established during development. In the somatosensory cortex, GABAergic interneurons born in the ventral telencephalon undergo protracted migration to reach their final postion in the cortex and acquire stereotypic morphologies before contacting their targets, the pyramidal cells and other interneurons. However, the cellular and molecular mechanisms that regulate interneuron maturation are poorly understood. In my talk, I will discuss the mechanisms by which gene expression and neuronal activity regulate the establishment of cortical interneuron subtypes, as well as their requisite laminar targeting and morphology. These questions will be examined through a combination of mouse genetics and physiology. The development of cortical interneuron diversity appears to arise through two sequential steps. We hypothesize that the initial specification of interneurons occurs at the progenitor stage and utilizes intrinsic genetic programs to divide them into approximately seven “cardinal” groups. Upon becoming postmitotic, immature interneurons migrate and integrate within distinct cortical regions. As they integrate into cortical plate, we have recently demonstrated that activity is selectively required for their selection of cortical laminae and morphological maturation. We suspect they are also receiving further signals that aid in their appropriate regional differentia-
tion. Our hope is that through these approaches the cellular logic underlying circuit maturation can be understood and provide a systematic approach for the visualization and targetted manipulation of interneuron excitability. As we believe that dysfunction of cortical interneurons underlies a variety of affective neurological disorders, our approach provides the means to explore the etiology of brain pathology. http://dx.doi.org/10.1016/j.ijdevneu.2012.10.093 ISDN2012 0272 Tortillas and toxins: Gene–environment fumonisin-induced neural tube defects
interactions
in
J. Gelineau-van Waes 1 , J. Maddox 1 , M. Rainey 1 , N. Gardner 1 , A. Sachs 1 , K. Voss 2 , R.T. Riley 2 1 Dept. of Pharmacology, Creighton University School of Medicine, Omaha, NE, United States 2 Toxicology and Mycotoxin Research Unit, USDA-ARS, Athens, GA, United States Fumonisin B1 (FB1) is a mycotoxin produced by a common fungal contaminant of maize. In populations that rely heavily on maize as a dietary staple, consumption of FB1-contaminated food during early pregnancy has been associated with increased risk for neural tube defects (NTDs). Administration of FB1 to pregnant LM/Bc mice causes exencephaly in 79% of exposed embryos. FB1 inhibits the enzyme ceramide synthase in de novo sphingolipid biosynthesis, resulting in decreased formation of ceramide and increased accumulation of sphinganine and its phosphorylated metabolite sphinganine-1-phosphate (Sa1P). Sa1P is a bioactive lipid mediator that functions as a ligand for a family of G protein-coupled ‘sphingosine-1-phosphate’ (S1P) receptors. Sa1P is significantly elevated in maternal blood spots, placenta, and amniotic fluid of LM/Bc mice after FB1 administration. Increased levels of Sa1P are also observed in cultured mouse neural progenitor cells treated with FB1. FTY720 is phosphorylated in vivo to form FTY720-P, which in turn functions as an S1P receptor agonist. Administration of FTY720 to pregnant SWV and LM/Bc mice causes 40–60% NTDs in exposed offspring, implicating a role for S1P receptor-mediated signaling in both FB1 and FTY720-induced NTDs. Lass1 is the gene that codes for the predominant isoform of ceramide synthase expressed in neural tissue. The Lass1 transcript is bicistronic with Gdf1 (growth differentiation factor 1), a member of the TGF superfamily. Inactivation of Gdf1 in knockout mice leads to increased expression of the remaining Lass1 portion of the Lass1–Gdf1 transcript. Conversely, FB1 inhibition of LASS1 results in increased Gdf1 expression in the open neural folds of exencephalic LM/Bc embryos, suggesting reciprocal feedback between Lass1 and Gdf1. Models for cross-talk between S1P receptor and TGF signaling pathways have been proposed. Cross-talk between Sa1P activation of S1P receptors and GDF1/Nodal/Activin signaling may be involved in the failure of neural tube closure after exposure to FB1.
http://dx.doi.org/10.1016/j.ijdevneu.2012.10.094 ISDN2012 0273 Phox2b and the viscero-somatic duality of the medulla Jean-Franc¸ois Brunet Institut de Biologie de l’École normale supérieure, ENS, 46 rue d’Ulm, 75005 Paris, France Taste and most sensory inputs required for the feedback regulation of digestive, respiratory and cardiovascular organs are conveyed to the central nervous system by so-called “visceral”