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      The Netrin-1/DCC guidance system: dopamine pathway maturation and psychiatric disorders emerging in adolescence

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          Abstract

          Axon guidance molecules direct growing axons toward their targets, assembling the intricate wiring of the nervous system. One of these molecules, Netrin-1, and its receptor, DCC (deleted in colorectal cancer), has profound effects, in laboratory animals, on the adolescent expansion of mesocorticolimbic pathways, particularly dopamine. Now, a rapidly growing literature suggests that (1) these same alterations could occur in humans, and (2) genetic variants in Netrin-1 and DCC are associated with depression, schizophrenia, and substance use. Together, these findings provide compelling evidence that Netrin-1 and DCC influence mesocorticolimbic-related psychopathological states that emerge during adolescence.

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          Most cited references 73

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          Molecular mechanisms of axon guidance.

           Laura Dickson (2002)
          Axons are guided along specific pathways by attractive and repulsive cues in the extracellular environment. Genetic and biochemical studies have led to the identification of highly conserved families of guidance molecules, including netrins, Slits, semaphorins, and ephrins. Guidance cues steer axons by regulating cytoskeletal dynamics in the growth cone through signaling pathways that are still only poorly understood. Elaborate regulatory mechanisms ensure that a given cue elicits the right response from the right axons at the right time but is otherwise ignored. With such regulatory mechanisms in place, a relatively small number of guidance factors can be used to generate intricate patterns of neuronal wiring.
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            Deleted in Colorectal Cancer (DCC) encodes a netrin receptor.

            The guidance of developing axons in the nervous system is mediated partly by diffusible chemoattractants secreted by axonal target cells. Netrins are chemoattractants for commissural axons in the vertebrate spinal cord, but the mechanisms through which they produce their effects are unknown. We show that Deleted in Colorectal Cancer (DCC), a transmembrane protein of the immunoglobulin superfamily, is expressed on spinal commissural axons and possesses netrin-1-binding activity. Moreover, an antibody to DCC selectively blocks the netrin-1-dependent outgrowth of commissural axons in vitro. These results indicate that DCC is a receptor or a component of a receptor that mediates the effects of netrin-1 on commissural axons, and they complement genetic evidence for interactions between DCC and netrin homologs in C. elegans and Drosophila.
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              Leveraging Polygenic Functional Enrichment to Improve GWAS Power

              Functional genomics data has the potential to increase GWAS power by identifying SNPs that have a higher prior probability of association. Here, we introduce a method that leverages polygenic functional enrichment to incorporate coding, conserved, regulatory, and LD-related genomic annotations into association analyses. We show via simulations with real genotypes that the method, functionally informed novel discovery of risk loci (FINDOR), correctly controls the false-positive rate at null loci and attains a 9%-38% increase in the number of independent associations detected at causal loci, depending on trait polygenicity and sample size. We applied FINDOR to 27 independent complex traits and diseases from the interim UK Biobank release (average N = 130K). Averaged across traits, we attained a 13% increase in genome-wide significant loci detected (including a 20% increase for disease traits) compared to unweighted raw p values that do not use functional data. We replicated the additional loci in independent UK Biobank and non-UK Biobank data, yielding a highly statistically significant replication slope (0.66-0.69) in each case. Finally, we applied FINDOR to the full UK Biobank release (average N = 416K), attaining smaller relative improvements (consistent with simulations) but larger absolute improvements, detecting an additional 583 GWAS loci. In conclusion, leveraging functional enrichment using our method robustly increases GWAS power.
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                Author and article information

                Contributors
                +514-761-6131 ext. 2814 , marco.leyton@mcgill.ca
                +514-761-6131 ext. 2814 , cecilia.flores@mcgill.ca
                Journal
                Mol Psychiatry
                Mol. Psychiatry
                Molecular Psychiatry
                Nature Publishing Group UK (London )
                1359-4184
                1476-5578
                28 October 2019
                28 October 2019
                2020
                : 25
                : 2
                : 297-307
                Affiliations
                [1 ]ISNI 0000 0004 1936 8649, GRID grid.14709.3b, Department of Psychiatry, , McGill University, ; Montreal, QC Canada
                [2 ]ISNI 0000 0004 1936 8649, GRID grid.14709.3b, Integrated Program in Neuroscience (IPN), , McGill University, ; Montreal, QC Canada
                [3 ]ISNI 0000 0004 1936 8649, GRID grid.14709.3b, Neurology and Neurosurgery, , McGill University, ; Montreal, QC Canada
                [4 ]ISNI 0000 0001 2353 5268, GRID grid.412078.8, Douglas Mental Health University Institute, ; Montreal, QC Canada
                [5 ]ISNI 0000 0004 0572 4702, GRID grid.414294.e, Present Address: Population Neuroscience and Developmental Neuroimaging, , Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, ; Toronto, ON Canada
                Article
                561
                10.1038/s41380-019-0561-7
                6974431
                31659271
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/100000026, U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA);
                Award ID: R01DA037911
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100002790, Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology);
                Award ID: 2982226
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100000024, Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada);
                Award ID: MOP-74709, 119543
                Award Recipient :
                Funded by: DV received scholarship support from Le Fonds de recherche du Québec – Santé (FRQS) and McGill University Faculty of Medicine Internal Studentship Awards (the Hugh E. Burke Fellowship and the James O. and Maria Meadows Fellowship).
                Funded by: FundRef https://doi.org/10.13039/501100007202, Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (Skin Research Training Centre);
                Award ID: MOP-119543, 133537, 152910
                Award Recipient :
                Categories
                Perspective
                Custom metadata
                © Springer Nature Limited 2020

                Molecular medicine

                depression, addiction, genetics, neuroscience, schizophrenia

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