{"publisher":"Springer Nature","oa_version":"Published Version","oa":1,"date_created":"2022-06-23T14:28:55Z","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","title":"WDFY3 mutation alters laminar position and morphology of cortical neurons","quality_controlled":"1","status":"public","related_material":{"link":[{"url":"https://doi.org/10.1186/s13229-023-00539-4","relation":"erratum"}]},"month":"06","article_processing_charge":"No","date_updated":"2023-08-03T07:21:32Z","tmp":{"image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"type":"journal_article","license":"https://creativecommons.org/licenses/by/4.0/","file":[{"content_type":"application/pdf","file_name":"2022_MolecularAutism_Schaaf.pdf","access_level":"open_access","creator":"dernst","relation":"main_file","checksum":"525d2618e855139089bbfc3e3d49d1b2","file_id":"11461","success":1,"file_size":7552298,"date_created":"2022-06-24T08:22:59Z","date_updated":"2022-06-24T08:22:59Z"}],"day":"22","department":[{"_id":"SiHi"}],"abstract":[{"text":"Background: Proper cerebral cortical development depends on the tightly orchestrated migration of newly born neurons from the inner ventricular and subventricular zones to the outer cortical plate. Any disturbance in this process during prenatal stages may lead to neuronal migration disorders (NMDs), which can vary in extent from focal to global. Furthermore, NMDs show a substantial comorbidity with other neurodevelopmental disorders, notably autism spectrum disorders (ASDs). Our previous work demonstrated focal neuronal migration defects in mice carrying loss-of-function alleles of the recognized autism risk gene WDFY3. However, the cellular origins of these defects in Wdfy3 mutant mice remain elusive and uncovering it will provide critical insight into WDFY3-dependent disease pathology.\r\nMethods: Here, in an effort to untangle the origins of NMDs in Wdfy3lacZ mice, we employed mosaic analysis with double markers (MADM). MADM technology enabled us to genetically distinctly track and phenotypically analyze mutant and wild-type cells concomitantly in vivo using immunofluorescent techniques.\r\nResults: We revealed a cell autonomous requirement of WDFY3 for accurate laminar positioning of cortical projection neurons and elimination of mispositioned cells during early postnatal life. In addition, we identified significant deviations in dendritic arborization, as well as synaptic density and morphology between wild type, heterozygous, and homozygous Wdfy3 mutant neurons in Wdfy3-MADM reporter mice at postnatal stages.\r\nLimitations: While Wdfy3 mutant mice have provided valuable insight into prenatal aspects of ASD pathology that remain inaccessible to investigation in humans, like most animal models, they do not a perfectly replicate all aspects of human ASD biology. The lack of human data makes it indeterminate whether morphological deviations described here apply to ASD patients or some of the other neurodevelopmental conditions associated with WDFY3 mutation.\r\nConclusions: Our genetic approach revealed several cell autonomous requirements of WDFY3 in neuronal development that could underlie the pathogenic mechanisms of WDFY3-related neurodevelopmental conditions. The results are also consistent with findings in other ASD animal models and patients and suggest an important role for WDFY3 in regulating neuronal function and interconnectivity in postnatal life.","lang":"eng"}],"date_published":"2022-06-22T00:00:00Z","publication_status":"published","year":"2022","intvolume":"        13","volume":13,"ddc":["570"],"keyword":["Psychiatry and Mental health","Developmental Biology","Developmental Neuroscience","Molecular Biology"],"isi":1,"file_date_updated":"2022-06-24T08:22:59Z","acknowledgement":"This study was funded by NIMH R21MH115347 to KSZ. KSZ is further supported by Shriners Hospitals for Children.\r\nWe would like to thank Angelo Harlan de Crescenzo for early contributions to this project.","external_id":{"isi":["000814641400001"]},"publication_identifier":{"issn":["2040-2392"]},"author":[{"first_name":"Zachary A.","last_name":"Schaaf","full_name":"Schaaf, Zachary A."},{"full_name":"Tat, Lyvin","first_name":"Lyvin","last_name":"Tat"},{"last_name":"Cannizzaro","first_name":"Noemi","full_name":"Cannizzaro, Noemi"},{"full_name":"Green, Ralph","last_name":"Green","first_name":"Ralph"},{"last_name":"Rülicke","first_name":"Thomas","full_name":"Rülicke, Thomas"},{"last_name":"Hippenmeyer","first_name":"Simon","id":"37B36620-F248-11E8-B48F-1D18A9856A87","full_name":"Hippenmeyer, Simon","orcid":"0000-0003-2279-1061"},{"first_name":"Konstantinos S.","last_name":"Zarbalis","full_name":"Zarbalis, Konstantinos S."}],"publication":"Molecular Autism","has_accepted_license":"1","doi":"10.1186/s13229-022-00508-3","_id":"11460","article_number":"27","language":[{"iso":"eng"}],"article_type":"original","citation":{"short":"Z.A. Schaaf, L. Tat, N. Cannizzaro, R. Green, T. Rülicke, S. Hippenmeyer, K.S. Zarbalis, Molecular Autism 13 (2022).","ista":"Schaaf ZA, Tat L, Cannizzaro N, Green R, Rülicke T, Hippenmeyer S, Zarbalis KS. 2022. WDFY3 mutation alters laminar position and morphology of cortical neurons. Molecular Autism. 13, 27.","apa":"Schaaf, Z. A., Tat, L., Cannizzaro, N., Green, R., Rülicke, T., Hippenmeyer, S., &#38; Zarbalis, K. S. (2022). WDFY3 mutation alters laminar position and morphology of cortical neurons. <i>Molecular Autism</i>. Springer Nature. <a href=\"https://doi.org/10.1186/s13229-022-00508-3\">https://doi.org/10.1186/s13229-022-00508-3</a>","chicago":"Schaaf, Zachary A., Lyvin Tat, Noemi Cannizzaro, Ralph Green, Thomas Rülicke, Simon Hippenmeyer, and Konstantinos S. Zarbalis. “WDFY3 Mutation Alters Laminar Position and Morphology of Cortical Neurons.” <i>Molecular Autism</i>. Springer Nature, 2022. <a href=\"https://doi.org/10.1186/s13229-022-00508-3\">https://doi.org/10.1186/s13229-022-00508-3</a>.","ama":"Schaaf ZA, Tat L, Cannizzaro N, et al. WDFY3 mutation alters laminar position and morphology of cortical neurons. <i>Molecular Autism</i>. 2022;13. doi:<a href=\"https://doi.org/10.1186/s13229-022-00508-3\">10.1186/s13229-022-00508-3</a>","ieee":"Z. A. Schaaf <i>et al.</i>, “WDFY3 mutation alters laminar position and morphology of cortical neurons,” <i>Molecular Autism</i>, vol. 13. Springer Nature, 2022.","mla":"Schaaf, Zachary A., et al. “WDFY3 Mutation Alters Laminar Position and Morphology of Cortical Neurons.” <i>Molecular Autism</i>, vol. 13, 27, Springer Nature, 2022, doi:<a href=\"https://doi.org/10.1186/s13229-022-00508-3\">10.1186/s13229-022-00508-3</a>."}}