Impact of the ADHD-susceptibility gene CDH13 on development and function of brain networks

Attention-deficit/hyperactivity disorder (ADHD) is a common, early onset and enduring neuropsychiatric disorder characterized by developmentally inappropriate inattention, hyperactivity, increased impulsivity and motivational/emotional dysregulation with similar prevalence rates throughout different cultural settings. Persistence of ADHD into adulthood is associated with considerable risk for co-morbidities such as depression and substance use disorder. Although the substantial heritability of ADHD is well documented the etiology is characterized by a complex coherence of genetic and environmental factors rendering identification of risk genes difficult. Genome-wide linkage as well as single nucleotide polymorphism (SNP) and copy-number variant (CNV) association scans recently allow to reliably define aetiopathogenesis-related genes. A considerable number of novel ADHD risk genes implicate biological processes involved in neurite outgrowth and axon guidance. Here, we focus on the gene encoding Cadherin-13 (CDH13), a cell adhesion molecule which was replicably associated with liability to ADHD and related neuropsychiatric conditions. Based on its unique expression pattern in the brain, we discuss the molecular structure and neuronal mechanisms of Cadherin-13 in relation to other cadherins and the cardiovascular system. An appraisal of various Cadherin-13-modulated signaling pathways impacting proliferation, migration and connectivity of specific neurons is also provided. Finally, we develop an integrative hypothesis of the mechanisms in which Cadherin-13 plays a central role in the regulation of brain network development, plasticity and function. The review concludes with emerging concepts about alterations in Cadherin-13 signaling contributing to the pathophysiology of neurodevelopmental disorders.

[1]  T. Wilens.  Effects of Methylphenidate on the Catecholaminergic System in Attention-Deficit/Hyperactivity Disorder , 2008, Journal of clinical psychopharmacology.

[2]  P. Erne,et al.  Integrin‐linked kinase is an essential mediator for T‐cadherin‐dependent signaling via Akt and GSK3β in endothelial cells , 2007 .

[3]  K. Lesch,et al.  Dances with black widow spiders: Dysregulation of glutamate signalling enters centre stage in ADHD , 2013, European Neuropsychopharmacology.

[4]  Carlos G. Dotti,et al.  Breaking the neuronal sphere: regulation of the actin cytoskeleton in neuritogenesis , 2002, Nature Reviews Neuroscience.

[5]  Y. Kodera,et al.  CDH13 promoter region is specifically methylated in poorly differentiated colorectal cancer , 2004, British Journal of Cancer.

[6]  H. Cline,et al.  Insulin receptor signaling in the development of neuronal structure and function , 2010, Neural Development.

[7]  B. Franke,et al.  CDH13 is associated with working memory performance in attention deficit/hyperactivity disorder , 2011, Genes, brain, and behavior.

[8]  L. Mei,et al.  BDNF-induced recruitment of TrkB receptor into neuronal lipid rafts , 2004, The Journal of cell biology.

[9]  C. Sandi,et al.  A Model for the Involvement of Neural Cell Adhesion Molecules in Stress-Related Mood Disorders , 2007, Neuroendocrinology.

[10]  T. Voyno-Yasenetskaya,et al.  T-cadherin is located in the nucleus and centrosomes in endothelial cells. , 2009, American journal of physiology. Cell physiology.

[11]  B. Honig,et al.  T-cadherin structures reveal a novel adhesive binding mechanism , 2010, Nature Structural &Molecular Biology.

[12]  阪井 満.  Frequent promoter methylation and gene silencing of CDH13 in pancreatic cancer , 2005 .

[13]  S. Price,et al.  Cadherins and catenins in synapse development , 2005, Current Opinion in Neurobiology.

[14]  M. Iyo,et al.  Genome-wide association for methamphetamine dependence: convergent results from 2 samples. , 2008, Archives of general psychiatry.

[15]  Fassnacht,et al.  Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree , 2011, Molecular Psychiatry.

[16]  S. Nelson,et al.  Family-based genome-wide association scan of attention-deficit/hyperactivity disorder. , 2010, Journal of the American Academy of Child and Adolescent Psychiatry.

[17]  B. Ranscht,et al.  T-cadherin, a novel cadherin cell adhesion molecule in the nervous system lacks the conserved cytoplasmic region , 1991, Neuron.

[18]  B. Angst,et al.  COMMENTARY The cadherin superfamily: diversity in form and function , 2022 .

[19]  C. Freitag,et al.  A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication. , 2010, Molecular psychiatry.

[20]  W. Ju,et al.  Control of Synaptic Strength, a Novel Function of Akt , 2003, Neuron.

[21]  Ramesh Srinivasan,et al.  Functional connectivity of frontal cortex in healthy and ADHD children reflected in EEG coherence. , 2007, Cerebral cortex.

[22]  A. Petridis,et al.  Physical and functional cooperation of neural cell adhesion molecule and β1-integrin in neurite outgrowth induction , 2011, Journal of Clinical Neuroscience.

[23]  David C. Turner,et al.  A neuronal cell line (PC12) expresses two β 1-class integrins—α 1 β 1, and α 3 β 1—that recognize different neurite outgrowth-promoting domains in laminin , 1990, Neuron.

[24]  B. Fredette,et al.  T-cadherin expression delineates specific regions of the developing motor axon-hindlimb projection pathway , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[25]  P. Erne,et al.  Integrin-linked kinase is an essential mediator for T-cadherin-dependent signaling via Akt and GSK3beta in endothelial cells. , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  P. Erne,et al.  Cadherins and cardiovascular disease. , 2009, Swiss medical weekly.

[27]  Aribert Rothenberger,et al.  Genome‐wide association scan of attention deficit hyperactivity disorder , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[28]  D. Karagogeos.  Neural GPI-anchored cell adhesion molecules. , 2003, Frontiers in bioscience : a journal and virtual library.

[29]  J. Sanes,et al.  Expression of Multiple Cadherins and Catenins in the Chick Optic Tectum , 1998, Molecular and Cellular Neuroscience.

[30]  J. Smoller,et al.  Molecular Genetics of Attention-Deficit/Hyperactivity Disorder , 2005, Biological Psychiatry.

[31]  Michael J. Frank,et al.  Testing Computational Models of Dopamine and Noradrenaline Dysfunction in Attention Deficit/Hyperactivity Disorder , 2007, Neuropsychopharmacology.

[32]  E. Bongarzone,et al.  Identification of Genes in the Oligodendrocyte Lineage through the Analysis of Conditionally Immortalized Cell Lines , 2002, Developmental Neuroscience.

[33]  P. Erne,et al.  Polarisation of T-cadherin to the leading edge of migrating vascular cells in vitro: a function in vascular cell motility? , 2003, Histochemistry and Cell Biology.

[34]  A. Sakurada,et al.  The H-cadherin (CDH13) gene is inactivated in human lung cancer , 1998, Human Genetics.

[35]  Nora D Volkow,et al.  Understanding the Effects of Stimulant Medications on Cognition in Individuals with Attention-Deficit Hyperactivity Disorder: A Decade of Progress , 2011, Neuropsychopharmacology.

[36]  P. Erne,et al.  Expression of cell adhesion molecule T-cadherin in the human vasculature , 2001, Histochemistry and Cell Biology.

[37]  Lawrence Shapiro,et al.  Specificity of cell-cell adhesion by classical cadherins: Critical role for low-affinity dimerization through beta-strand swapping. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[38]  George Bush,et al.  Attention-Deficit/Hyperactivity Disorder and Attention Networks , 2010, Neuropsychopharmacology.

[39]  M. McInnis,et al.  Psychiatric genetics: progress amid controversy , 2008, Nature Reviews Genetics.

[40]  Y. Kodera,et al.  Methylation pattern of CDH13 gene in digestive tract cancers , 2004, British Journal of Cancer.

[41]  George Bush,et al.  Cingulate, Frontal, and Parietal Cortical Dysfunction in Attention-Deficit/Hyperactivity Disorder , 2011, Biological Psychiatry.

[42]  K. Lesch,et al.  A lifetime of attention-deficit/hyperactivity disorder: diagnostic challenges, treatment and neurobiological mechanisms , 2011, Expert review of neurotherapeutics.

[43]  M. Takeichi.  The cadherin superfamily in neuronal connections and interactions , 2007, Nature Reviews Neuroscience.

[44]  M. Solanto.  Dopamine dysfunction in AD/HD: integrating clinical and basic neuroscience research , 2002, Behavioural Brain Research.

[45]  Aribert Rothenberger,et al.  Genome‐wide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[46]  M. Bronner‐Fraser,et al.  T-cadherin expression alternates with migrating neural crest cells in the trunk of the avian embryo. , 1991, Development.

[47]  Katya Rubia,et al.  “Cool” Inferior Frontostriatal Dysfunction in Attention-Deficit/Hyperactivity Disorder Versus “Hot” Ventromedial Orbitofrontal-Limbic Dysfunction in Conduct Disorder: A Review , 2011, Biological Psychiatry.

[48]  David A Lewis,et al.  A molecular signature of depression in the amygdala. , 2009, The American journal of psychiatry.

[49]  S. Cichon,et al.  Genome-wide association study of alcohol dependence. , 2009, Archives of general psychiatry.

[50]  John F. Peden,et al.  Thirty-five common variants for coronary artery disease: the fruits of much collaborative labour , 2011, Human molecular genetics.

[51]  Vincent Giampietro,et al.  Reduced activation and inter-regional functional connectivity of fronto-striatal networks in adults with childhood Attention-Deficit Hyperactivity Disorder (ADHD) and persisting symptoms during tasks of motor inhibition and cognitive switching. , 2010, Journal of psychiatric research.

[52]  P. Erne,et al.  RhoA and Rac mediate endothelial cell polarization and detachment induced by T‐cadherin , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[53]  Oscar Vilarroya,et al.  Ventro-Striatal Reductions Underpin Symptoms of Hyperactivity and Impulsivity in Attention-Deficit/Hyperactivity Disorder , 2009, Biological Psychiatry.

[54]  P. Erne,et al.  A guide and guard: the many faces of T-cadherin. , 2009, Cellular signalling.

[55]  Patrick F. Sullivan,et al.  Don't give up on GWAS , 2012, Molecular Psychiatry.

[56]  MariaPhilippova,et al.  Atypical GPI-Anchored T-Cadherin Stimulates Angiogenesis In Vitro and In Vivo , 2006 .

[57]  Susanne Walitza,et al.  Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder , 2011, Nature Genetics.

[58]  P. Erne,et al.  T-cadherin upregulation correlates with cell-cycle progression and promotes proliferation of vascular cells. , 2004, Cardiovascular research.

[59]  Natalia del Campo,et al.  The Roles of Dopamine and Noradrenaline in the Pathophysiology and Treatment of Attention-Deficit/Hyperactivity Disorder , 2011, Biological Psychiatry.

[60]  Susanne Walitza,et al.  Genome-Wide Analysis of Copy Number Variants in Attention Deficit Hyperactivity Disorder: The Role of Rare Variants and Duplications at 15q13.3 , 2012, The American journal of psychiatry.

[61]  Francis S Collins,et al.  A HapMap harvest of insights into the genetics of common disease. , 2008, The Journal of clinical investigation.

[62]  P. Erne,et al.  Cell adhesion molecule T-cadherin regulates vascular cell adhesion, phenotype and motility. , 2004, Experimental cell research.

[63]  Sarah Durston,et al.  Decreased frontostriatal microstructural organization in attention deficit/hyperactivity disorder , 2012, Human brain mapping.

[64]  N. Singewald,et al.  Release of neurotransmitters in the locus coeruleus , 1998, Progress in Neurobiology.

[65]  N. Volkow,et al.  Abnormal Functional Connectivity in Children with Attention-Deficit/Hyperactivity Disorder , 2012, Biological Psychiatry.

[66]  V. Berezin,et al.  Signaling mechanisms of neurite outgrowth induced by the cell adhesion molecules NCAM and N-Cadherin , 2008, Cellular and Molecular Life Sciences.

[67]  P. Goldman-Rakic.  Regional and cellular fractionation of working memory. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[68]  J. Lupski,et al.  Clan Genomics and the Complex Architecture of Human Disease , 2011, Cell.

[69]  G. Rougon,et al.  Axonal Molecules of the Immunoglobulin Superfamily Bearing a GPI Anchor: Their Role in Controlling Neurite Outgrowth , 1997, Molecular and Cellular Neuroscience.

[70]  R. Heimark,et al.  Cloning of five human cadherins clarifies characteristic features of cadherin extracellular domain and provides further evidence for two structurally different types of cadherin. , 1994, Cell adhesion and communication.

[71]  Eric C. Griffith,et al.  An RNAi-Based Approach Identifies Molecules Required for Glutamatergic and GABAergic Synapse Development , 2007, Neuron.

[72]  F. van Roy,et al.  Phylogenetic analysis of the cadherin superfamily allows identification of six major subfamilies besides several solitary members. , 2000, Journal of molecular biology.

[73]  P. Erne,et al.  Identification of Proteins Associating with Glycosylphosphatidylinositol- Anchored T-Cadherin on the Surface of Vascular Endothelial Cells: Role for Grp78/BiP in T-Cadherin-Dependent Cell Survival , 2008, Molecular and Cellular Biology.

[74]  Kozo Kaibuchi,et al.  Rho-family GTPases in cadherin-mediated cell — cell adhesion , 2001, Nature Reviews Molecular Cell Biology.

[75]  M. Daly,et al.  Genome‐wide association scan of the time to onset of attention deficit hyperactivity disorder , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[76]  A. Gorman,et al.  Involvement of Akt in neurite outgrowth , 2009, Cellular and Molecular Life Sciences.

[77]  S. Foote,et al.  Efferent projections of nucleus locus coeruleus: Morphologic subpopulations have different efferent targets , 1986, Neuroscience.

[78]  C. Greer,et al.  Cadherin expression in the developing mouse olfactory system , 2007, The Journal of comparative neurology.

[79]  G. Abecasis,et al.  Genome-wide association scan for five major dimensions of personality , 2010, Molecular Psychiatry.

[80]  Chuan-Yun Li,et al.  Molecular Genetics of Addiction and Related Heritable Phenotypes , 2008, Annals of the New York Academy of Sciences.

[81]  B. Franke,et al.  The genetics of attention deficit/hyperactivity disorder in adults, a review , 2011, Molecular Psychiatry.

[82]  R. Cardiff,et al.  T-cadherin supports angiogenesis and adiponectin association with the vasculature in a mouse mammary tumor model. , 2008, Cancer research.

[83]  John Wei,et al.  Identify Risk Genes for ADHD Rare Copy Number Variation Discovery and Cross-Disorder Comparisons , 2011 .

[84]  K. Ghoshal,et al.  Identification of T-cadherin as a Novel Target of DNA Methyltransferase 3B and Its Role in the Suppression of Nerve Growth Factor-mediated Neurite Outgrowth in PC12 Cells* , 2006, Journal of Biological Chemistry.

[85]  M. Daly,et al.  Case-control genome-wide association study of attention-deficit/hyperactivity disorder. , 2010, Journal of the American Academy of Child and Adolescent Psychiatry.

[86]  M. Gill,et al.  Investigating the Contribution of Common Genetic Variants to the Risk and Pathogenesis of ADHD , 2012, The American journal of psychiatry.

[87]  P. Erne,et al.  T‐cadherin protects endothelial cells from oxidative stress‐induced apoptosis , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[88]  B. Fredette,et al.  Inhibition of motor axon growth by T-cadherin substrata. , 1996, Development.

[89]  Jing Xu,et al.  Additive neuroprotection of GABA A and GABA B receptor agonists in cerebral ischemic injury via PI-3K/Akt pathway inhibiting the ASK1-JNK cascade , 2008, Neuropharmacology.

[90]  S. Faraone,et al.  Meta-Analysis of Structural Imaging Findings in Attention-Deficit/Hyperactivity Disorder , 2007, Biological Psychiatry.

[91]  Fazil Aliev,et al.  Genome-wide association study of comorbid depressive syndrome and alcohol dependence , 2012, Psychiatric genetics.

[92]  W. Gallin,et al.  In the First Extracellular Domain of E-cadherin, Heterophilic Interactions, but Not the Conserved His-Ala-Val Motif, Are Required for Adhesion* , 2002, The Journal of Biological Chemistry.

[93]  B. Franke,et al.  Integrated genome-wide association study findings: identification of a neurodevelopmental network for attention deficit hyperactivity disorder. , 2011, The American journal of psychiatry.

[94]  D. Kipmen-Korgun,et al.  T-Cadherin Mediates Low-Density Lipoprotein-Initiated Cell Proliferation Via the Ca2+-Tyrosine Kinase-Erk1/2 Pathway , 2005, Journal of cardiovascular pharmacology.

[95]  S. Cichon,et al.  Genome‐wide association study in German patients with attention deficit/hyperactivity disorder , 2011, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[96]  Kathryn Roeder,et al.  Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism , 2011, Neuron.

[97]  P. Erne,et al.  Extracellular Cadherin repeat domains EC1 and EC5 of T‐cadherin are essential for its ability to stimulate angiogenic behavior of endothelial cells , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[98]  H. Lodish,et al.  T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[99]  Pedro Iglesias,et al.  The role of the novel adipocyte-derived hormone adiponectin in human disease. , 2003, European journal of endocrinology.

[100]  Y. Ohtsuki,et al.  Expression of T‐Cadherin (CDH13, H‐Cadherin) in Human Brain and Its Characteristics as a Negative Growth Regulator of Epidermal Growth Factor in Neuroblastoma Cells , 2000, Journal of neurochemistry.

[101]  S. Grzesiek,et al.  Insights into the Low Adhesive Capacity of Human T-cadherin from the NMR Structure of Its N-terminal Extracellular Domain* , 2008, Journal of Biological Chemistry.

[102]  Allan R. Jones,et al.  The Allen Brain Atlas: 5 years and beyond , 2009, Nature Reviews Neuroscience.

[103]  A. Arnsten.  Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks , 2011, Biological Psychiatry.

[104]  B. Lu,et al.  Activity-dependent modulation of the BDNF receptor TrkB: mechanisms and implications , 2005, Trends in Neurosciences.

[105]  G. Tsujimoto,et al.  Identification of three human type-II classic cadherins and frequent heterophilic interactions between different subclasses of type-II classic cadherins. , 2000, The Biochemical journal.

[106]  Sam W. Lee.  H–cadherin, a novel cadherin with growth inhibitory functions and diminished expression in human breast cancer , 1996, Nature Medicine.

[107]  A. Andreeva,et al.  Cadherin 13 in cancer , 2010, Genes, chromosomes & cancer.

[108]  Kerstin Konrad,et al.  Is the ADHD brain wired differently? A review on structural and functional connectivity in attention deficit hyperactivity disorder , 2010, Human brain mapping.

[109]  J. Barrett,et al.  Genetic risk prediction in complex disease , 2011, Human molecular genetics.

[110]  T. Arumugam,et al.  Adiponectin receptor signalling in the brain , 2012, British journal of pharmacology.

[111]  F. Castellanos.  Toward the Dimensionome: Parsing Reward-Related Processing in Attention-Deficit/Hyperactivity Disorder , 2009, Biological Psychiatry.

[112]  A. Hall,et al.  Rho GTPases in cell biology , 2002, Nature.

[113]  Kai Simons,et al.  Lipid rafts and signal transduction , 2000, Nature Reviews Molecular Cell Biology.

[114]  M. Owen,et al.  Advances in genetic findings on attention deficit hyperactivity disorder , 2007, Psychological Medicine.

[115]  B. Franke,et al.  Meta‐analysis of genome‐wide linkage scans of attention deficit hyperactivity disorder , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[116]  Elisabeth Bock,et al.  Regulators of Neurite Outgrowth: Role of Cell Adhesion Molecules , 2004, Annals of the New York Academy of Sciences.

[117]  Susanne Walitza,et al.  Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies , 2008, Journal of Neural Transmission.

[118]  Katya Rubia,et al.  Structural and functional brain imaging in adult attention-deficit/hyperactivity disorder , 2010, Expert review of neurotherapeutics.

[119]  K. Lesch,et al.  Co-morbidity of adult attention-deficit/hyperactivity disorder with focus on personality traits and related disorders in a tertiary referral center , 2007, European Archives of Psychiatry and Clinical Neuroscience.

[120]  Benjamin M. Neale,et al.  Genome-wide association studies in ADHD , 2009, Human Genetics.

[121]  Susanne Walitza,et al.  Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder. , 2010, Journal of the American Academy of Child and Adolescent Psychiatry.

[122]  P. Ruiz-Lozano,et al.  T-cadherin is critical for adiponectin-mediated cardioprotection in mice. , 2010, The Journal of clinical investigation.