Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain
Background: During early prenatal stages of brain development, serotonin (5-HT)-specific neurons migrate through somal translocation to form the raphe nuclei and subsequently begin to project to their target regions. The rostral cluster of cells, comprising the median and dorsal raphe (DR), innervat...
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| Format: | Article |
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Frontiers Media S.A.
2017-09-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fncel.2017.00307/full |
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| author | Andrea Forero Olga Rivero Sina Wäldchen Hsing-Ping Ku Dominik P. Kiser Yvonne Gärtner Laura S. Pennington Jonas Waider Patricia Gaspar Charline Jansch Frank Edenhofer Frank Edenhofer Thérèse J. Resink Robert Blum Markus Sauer Klaus-Peter Lesch Klaus-Peter Lesch Klaus-Peter Lesch |
| author_facet | Andrea Forero Olga Rivero Sina Wäldchen Hsing-Ping Ku Dominik P. Kiser Yvonne Gärtner Laura S. Pennington Jonas Waider Patricia Gaspar Charline Jansch Frank Edenhofer Frank Edenhofer Thérèse J. Resink Robert Blum Markus Sauer Klaus-Peter Lesch Klaus-Peter Lesch Klaus-Peter Lesch |
| author_sort | Andrea Forero |
| collection | DOAJ |
| description | Background: During early prenatal stages of brain development, serotonin (5-HT)-specific neurons migrate through somal translocation to form the raphe nuclei and subsequently begin to project to their target regions. The rostral cluster of cells, comprising the median and dorsal raphe (DR), innervates anterior regions of the brain, including the prefrontal cortex. Differential analysis of the mouse 5-HT system transcriptome identified enrichment of cell adhesion molecules in 5-HT neurons of the DR. One of these molecules, cadherin-13 (Cdh13) has been shown to play a role in cell migration, axon pathfinding, and synaptogenesis. This study aimed to investigate the contribution of Cdh13 to the development of the murine brain 5-HT system.Methods: For detection of Cdh13 and components of the 5-HT system at different embryonic developmental stages of the mouse brain, we employed immunofluorescence protocols and imaging techniques, including epifluorescence, confocal and structured illumination microscopy. The consequence of CDH13 loss-of-function mutations on brain 5-HT system development was explored in a mouse model of Cdh13 deficiency.Results: Our data show that in murine embryonic brain Cdh13 is strongly expressed on 5-HT specific neurons of the DR and in radial glial cells (RGCs), which are critically involved in regulation of neuronal migration. We observed that 5-HT neurons are intertwined with these RGCs, suggesting that these neurons undergo RGC-guided migration. Cdh13 is present at points of intersection between these two cell types. Compared to wildtype controls, Cdh13-deficient mice display increased cell densities in the DR at embryonic stages E13.5, E17.5, and adulthood, and higher serotonergic innervation of the prefrontal cortex at E17.5.Conclusion: Our findings provide evidence for a role of CDH13 in the development of the serotonergic system in early embryonic stages. Specifically, we indicate that Cdh13 deficiency affects the cell density of the developing DR and the posterior innervation of the prefrontal cortex (PFC), and therefore might be involved in the migration, axonal outgrowth and terminal target finding of DR 5-HT neurons. Dysregulation of CDH13 expression may thus contribute to alterations in this system of neurotransmission, impacting cognitive function, which is frequently impaired in neurodevelopmental disorders including attention-deficit/hyperactivity and autism spectrum disorders. |
| first_indexed | 2024-04-13T13:04:46Z |
| format | Article |
| id | doaj.art-03b246aff9ba4670b540acf15d9bfd86 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-04-13T13:04:46Z |
| publishDate | 2017-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-03b246aff9ba4670b540acf15d9bfd862022-12-22T02:45:48ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022017-09-011110.3389/fncel.2017.00307269594Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse BrainAndrea Forero0Olga Rivero1Sina Wäldchen2Hsing-Ping Ku3Dominik P. Kiser4Yvonne Gärtner5Laura S. Pennington6Jonas Waider7Patricia Gaspar8Charline Jansch9Frank Edenhofer10Frank Edenhofer11Thérèse J. Resink12Robert Blum13Markus Sauer14Klaus-Peter Lesch15Klaus-Peter Lesch16Klaus-Peter Lesch17Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, GermanyDivision of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, GermanyDepartment of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, GermanyDivision of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, GermanyDivision of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, GermanyDivision of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, GermanyDivision of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, GermanyDivision of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, GermanyInstitut du Fer á Moulin, Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S839, Paris, FranceDivision of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, GermanyDepartment of Genomics, Stem Cell Biology and Regenerative Medicine, Institute of Molecular Biology and Center for Molecular Biosciences Innsbruck (CMBI), Leopold-Franzens-University Innsbruck, Innsbruck, AustriaStem Cell Biology and Regenerative Medicine Group, Institute of Anatomy and Cell Biology, Julius-Maximilians-University of Würzburg, Würzburg, GermanyLaboratory for Signal Transduction, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, SwitzerlandDepartment of Clinical Neurobiology, University of Würzburg, Würzburg, GermanyDepartment of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, GermanyDivision of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, GermanyLaboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I. M. Sechenov First Moscow State Medical University, Moscow, RussiaDepartment of Translational Neuroscience, School of Mental Health and Neuroscience, Maastricht University, Maastricht, NetherlandsBackground: During early prenatal stages of brain development, serotonin (5-HT)-specific neurons migrate through somal translocation to form the raphe nuclei and subsequently begin to project to their target regions. The rostral cluster of cells, comprising the median and dorsal raphe (DR), innervates anterior regions of the brain, including the prefrontal cortex. Differential analysis of the mouse 5-HT system transcriptome identified enrichment of cell adhesion molecules in 5-HT neurons of the DR. One of these molecules, cadherin-13 (Cdh13) has been shown to play a role in cell migration, axon pathfinding, and synaptogenesis. This study aimed to investigate the contribution of Cdh13 to the development of the murine brain 5-HT system.Methods: For detection of Cdh13 and components of the 5-HT system at different embryonic developmental stages of the mouse brain, we employed immunofluorescence protocols and imaging techniques, including epifluorescence, confocal and structured illumination microscopy. The consequence of CDH13 loss-of-function mutations on brain 5-HT system development was explored in a mouse model of Cdh13 deficiency.Results: Our data show that in murine embryonic brain Cdh13 is strongly expressed on 5-HT specific neurons of the DR and in radial glial cells (RGCs), which are critically involved in regulation of neuronal migration. We observed that 5-HT neurons are intertwined with these RGCs, suggesting that these neurons undergo RGC-guided migration. Cdh13 is present at points of intersection between these two cell types. Compared to wildtype controls, Cdh13-deficient mice display increased cell densities in the DR at embryonic stages E13.5, E17.5, and adulthood, and higher serotonergic innervation of the prefrontal cortex at E17.5.Conclusion: Our findings provide evidence for a role of CDH13 in the development of the serotonergic system in early embryonic stages. Specifically, we indicate that Cdh13 deficiency affects the cell density of the developing DR and the posterior innervation of the prefrontal cortex (PFC), and therefore might be involved in the migration, axonal outgrowth and terminal target finding of DR 5-HT neurons. Dysregulation of CDH13 expression may thus contribute to alterations in this system of neurotransmission, impacting cognitive function, which is frequently impaired in neurodevelopmental disorders including attention-deficit/hyperactivity and autism spectrum disorders.http://journal.frontiersin.org/article/10.3389/fncel.2017.00307/fullserotonincadherin-13 (CDH13)T-cadherinneurodevelopmentpsychiatric disordersradial glia |
| spellingShingle | Andrea Forero Olga Rivero Sina Wäldchen Hsing-Ping Ku Dominik P. Kiser Yvonne Gärtner Laura S. Pennington Jonas Waider Patricia Gaspar Charline Jansch Frank Edenhofer Frank Edenhofer Thérèse J. Resink Robert Blum Markus Sauer Klaus-Peter Lesch Klaus-Peter Lesch Klaus-Peter Lesch Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain Frontiers in Cellular Neuroscience serotonin cadherin-13 (CDH13) T-cadherin neurodevelopment psychiatric disorders radial glia |
| title | Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain |
| title_full | Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain |
| title_fullStr | Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain |
| title_full_unstemmed | Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain |
| title_short | Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain |
| title_sort | cadherin 13 deficiency increases dorsal raphe 5 ht neuron density and prefrontal cortex innervation in the mouse brain |
| topic | serotonin cadherin-13 (CDH13) T-cadherin neurodevelopment psychiatric disorders radial glia |
| url | http://journal.frontiersin.org/article/10.3389/fncel.2017.00307/full |
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