@article{ZieglerEhlisWeberetal.2021,
  author    = {Ziegler, Georg C. and Ehlis, Ann-Christine and Weber, Heike and Vitale, Maria Rosaria and Z{\"o}ller, Johanna E. M. and Ku, Hsing-Ping and Schiele, Miriam A. and K{\"u}rbitz, Laura I. and Romanos, Marcel and Pauli, Paul and Kalisch, Raffael and Zwanzger, Peter and Domschke, Katharina and Fallgatter, Andreas J. and Reif, Andreas and Lesch, Klaus-Peter},
  title     = {A Common CDH13 Variant is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD},
  series = {Genes},
  volume    = {12},
  journal   = {Genes},
  number    = {9},
  issn      = {2073-4425},
  doi       = {10.3390/genes12091356},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245220},
  year      = {2021},
  abstract  = {The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.},
  language  = {en}
}
@article{ZieglerAlmosMcNeilletal.2020,
  author    = {Ziegler, Georg C. and Almos, Peter and McNeill, Rhiannon V. and Jansch, Charline and Lesch, Klaus-Peter},
  title     = {Cellular effects and clinical implications of SLC2A3 copy number variation},
  series = {Journal of Cellular Physiology},
  volume    = {235},
  journal   = {Journal of Cellular Physiology},
  number    = {12},
  doi       = {10.1002/jcp.29753},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218009},
  pages     = {9021 -- 9036},
  year      = {2020},
  abstract  = {SLC2A3 encodes the predominantly neuronal glucose transporter 3 (GLUT3), which facilitates diffusion of glucose across plasma membranes. The human brain depends on a steady glucose supply for ATP generation, which consequently fuels critical biochemical processes, such as axonal transport and neurotransmitter release. Besides its role in the central nervous system, GLUT3 is also expressed in nonneural organs, such as the heart and white blood cells, where it is equally involved in energy metabolism. In cancer cells, GLUT3 overexpression contributes to the Warburg effect by answering the cell's increased glycolytic demands. The SLC2A3 gene locus at chromosome 12p13.31 is unstable and prone to non-allelic homologous recombination events, generating multiple copy number variants (CNVs) of SLC2A3 which account for alterations in SLC2A3 expression. Recent associations of SLC2A3 CNVs with different clinical phenotypes warrant investigation of the potential influence of these structural variants on pathomechanisms of neuropsychiatric, cardiovascular, and immune diseases. In this review, we accumulate and discuss the evidence how SLC2A3 gene dosage may exert diverse protective or detrimental effects depending on the pathological condition. Cellular states which lead to increased energetic demand, such as organ development, proliferation, and cellular degeneration, appear particularly susceptible to alterations in SLC2A3 copy number. We conclude that better understanding of the impact of SLC2A3 variation on disease etiology may potentially provide novel therapeutic approaches specifically targeting this GLUT.},
  language  = {en}
}
@phdthesis{ForeroEcheverry2020,
  author    = {Forero Echeverry, Andrea Marcela},
  title     = {Impact of Cadherin-13 deficiency on the brain serotonin system using mouse models and human iPSC-derived neurons},
  doi       = {10.25972/OPUS-21659},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216592},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2020},
  abstract  = {Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter involved in early developmental processes such as cell proliferation, migration, and differentiation. Recent research in humans showed that the brain 5-HT system and CDH13 are interlinked in the genetics of neurodevelopmental disorders including attention- deficit/hyperactivity disorder and autism spectrum disorder (Lesch et al., 2008; Neale et al., 2008; Neale, Medland, Ripke, Anney, et al., 2010; Neale, Medland, Ripke, Asherson, et al., 2010; Sanders et al., 2011; Sanders et al., 2015; Zhou et al., 2008). This study introduces Cadherin-13 (CDH13), a cell adhesion protein, as a contributor to the development and function of the 5-HT system. Our experiments show that the absence of CDH13 increases the density of 5-HT neurons in the developing dorsal raphe (DR) and increases the 5-HT innervation of the prefrontal cortex in mouse embryonic stages. CDH13 is also observed in radial glial cells, an important progenitor cell type linked to neuronal migration. A three-dimensional reconstruction carried out with super-resolution microscopy, identifies 5-HT neurons intertwined with radial glial cells, and CDH13 clusters at contact points between these cells. This indicates a potential contribution of CDH13 to the migration of DR 5-HT neurons. As CDH13 is strongly expressed in 5-HT neurons, we asked whether the selective deletion of CDH13 from these cells is sufficient to generate the alterations observed in the Cdh13 constitutive knockout mouse line. In 5-HT conditional Cdh13 knockout mice (Cdh13 cKO) an increase in DR 5-HT neurons in the embryonic and adult brains is observed, as well as 5-HT hyperinnervation of cortical regions. Therefore, illustrating that the lack of CDH13 from 5-HT neurons alone impacts DR formation and serotonergic innervation. Behavioral testing conducted on Cdh13 cKO mice showed delayed learning in visuospatial learning and memory processing, as well as, changes in sociability parameters. To find out how CDH13 localizes in human 5-HT neurons, CDH13 was visualized in neurons that derived from human induced pluripotent stem cells (iPSC). Super-resolution microscopy confirmed CDH13 expression in a subgroup of induced human neurons positive for typical hallmarks of 5-HT neurons, such as expression of Tph2, the neuron-specific tryptophan hydroxylase, and synaptic structures. In summary, the work included in this thesis presents a detailed analysis of CDH13 expression and localization in the 5-HT system and shows that deletion of CDH13 from 5-HT neurons affects specific higher-order functions of the brain.},
  language  = {en}
}
@article{FereroRiveroWaeldchenetal.2017,
  author    = {Ferero, Andrea and Rivero, Olga and W{\"a}ldchen, Sina and Ku, Hsing-Ping and Kiser, Dominik P. and G{\"a}rtner, Yvonne and Pennington, Laura S. and Waider, Jonas and Gaspar, Patricia and Jansch, Charline and Edenhofer, Frank and Resink, Th{\´e}r{\`e}se J. and Blum, Robert and Sauer, Markus and Lesch, Klaus-Peter},
  title     = {Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain},
  series = {Frontiers in Cellular Neuroscience},
  volume    = {11},
  journal   = {Frontiers in Cellular Neuroscience},
  number    = {307},
  doi       = {10.3389/fncel.2017.00307},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170313},
  year      = {2017},
  abstract  = {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.},
  language  = {en}
}