[{"language":[{"iso":"eng"}],"publisher":"Springer Nature","article_type":"original","date_published":"2021-05-24T00:00:00Z","month":"05","file":[{"access_level":"open_access","date_updated":"2021-05-28T12:39:43Z","file_size":9358599,"file_name":"2021_NatureCommunications_Morandell.pdf","checksum":"337e0f7959c35ec959984cacdcb472ba","date_created":"2021-05-28T12:39:43Z","relation":"main_file","content_type":"application/pdf","file_id":"9430","creator":"kschuh","success":1}],"date_created":"2021-05-28T11:49:46Z","department":[{"_id":"GaNo"},{"_id":"JoDa"},{"_id":"FlSc"},{"_id":"MiSi"},{"_id":"LifeSc"},{"_id":"Bio"}],"license":"https://creativecommons.org/licenses/by/4.0/","has_accepted_license":"1","status":"public","intvolume":"        12","type":"journal_article","day":"24","file_date_updated":"2021-05-28T12:39:43Z","issue":"1","publication":"Nature Communications","external_id":{"isi":["000658769900010"]},"title":"Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development","ec_funded":1,"acknowledged_ssus":[{"_id":"PreCl"}],"doi":"10.1038/s41467-021-23123-x","year":"2021","ddc":["572"],"related_material":{"link":[{"url":"https://ist.ac.at/en/news/defective-gene-slows-down-brain-cells/","relation":"press_release"}],"record":[{"relation":"earlier_version","id":"7800","status":"public"},{"status":"public","relation":"dissertation_contains","id":"12401"}]},"isi":1,"article_number":"3058","tmp":{"image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"keyword":["General Biochemistry","Genetics and Molecular Biology"],"author":[{"first_name":"Jasmin","last_name":"Morandell","full_name":"Morandell, Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Lena A","full_name":"Schwarz, Lena A","last_name":"Schwarz","id":"29A8453C-F248-11E8-B48F-1D18A9856A87"},{"orcid":"0000-0003-1843-3173","last_name":"Basilico","full_name":"Basilico, Bernadette","first_name":"Bernadette","id":"36035796-5ACA-11E9-A75E-7AF2E5697425"},{"id":"4323B49C-F248-11E8-B48F-1D18A9856A87","first_name":"Saren","last_name":"Tasciyan","full_name":"Tasciyan, Saren","orcid":"0000-0003-1671-393X"},{"id":"38C393BE-F248-11E8-B48F-1D18A9856A87","last_name":"Dimchev","full_name":"Dimchev, Georgi A","orcid":"0000-0001-8370-6161","first_name":"Georgi A"},{"last_name":"Nicolas","full_name":"Nicolas, Armel","first_name":"Armel","id":"2A103192-F248-11E8-B48F-1D18A9856A87"},{"orcid":"0000-0003-1216-9105","last_name":"Sommer","full_name":"Sommer, Christoph M","first_name":"Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Caroline","full_name":"Kreuzinger, Caroline","last_name":"Kreuzinger","id":"382077BA-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Christoph","last_name":"Dotter","full_name":"Dotter, Christoph","orcid":"0000-0002-9033-9096","id":"4C66542E-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Knaus","full_name":"Knaus, Lisa","first_name":"Lisa","id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Zoe","last_name":"Dobler","full_name":"Dobler, Zoe","id":"D23090A2-9057-11EA-883A-A8396FC7A38F"},{"full_name":"Cacci, Emanuele","last_name":"Cacci","first_name":"Emanuele"},{"orcid":"0000-0003-4790-8078","last_name":"Schur","full_name":"Schur, Florian KM","first_name":"Florian KM","id":"48AD8942-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Johann G","orcid":"0000-0001-8559-3973","full_name":"Danzl, Johann G","last_name":"Danzl","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87"},{"id":"3E57A680-F248-11E8-B48F-1D18A9856A87","full_name":"Novarino, Gaia","last_name":"Novarino","orcid":"0000-0002-7673-7178","first_name":"Gaia"}],"abstract":[{"lang":"eng","text":"De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 lead to autism spectrum disorder (ASD). In mouse, constitutive haploinsufficiency leads to motor coordination deficits as well as ASD-relevant social and cognitive impairments. However, induction of Cul3 haploinsufficiency later in life does not lead to ASD-relevant behaviors, pointing to an important role of Cul3 during a critical developmental window. Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities. At the molecular level, we found that Cul3 controls neuronal migration by tightly regulating the amount of Plastin3 (Pls3), a previously unrecognized player of neural migration. Furthermore, we found that Pls3 cell-autonomously regulates cell migration by regulating actin cytoskeleton organization, and its levels are inversely proportional to neural migration speed. Finally, we provide evidence that cellular phenotypes associated with autism-linked gene haploinsufficiency can be rescued by transcriptional activation of the intact allele in vitro, offering a proof of concept for a potential therapeutic approach for ASDs."}],"publication_status":"published","citation":{"chicago":"Morandell, Jasmin, Lena A Schwarz, Bernadette Basilico, Saren Tasciyan, Georgi A Dimchev, Armel Nicolas, Christoph M Sommer, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” <i>Nature Communications</i>. Springer Nature, 2021. <a href=\"https://doi.org/10.1038/s41467-021-23123-x\">https://doi.org/10.1038/s41467-021-23123-x</a>.","ieee":"J. Morandell <i>et al.</i>, “Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development,” <i>Nature Communications</i>, vol. 12, no. 1. Springer Nature, 2021.","apa":"Morandell, J., Schwarz, L. A., Basilico, B., Tasciyan, S., Dimchev, G. A., Nicolas, A., … Novarino, G. (2021). Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. <i>Nature Communications</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41467-021-23123-x\">https://doi.org/10.1038/s41467-021-23123-x</a>","short":"J. Morandell, L.A. Schwarz, B. Basilico, S. Tasciyan, G.A. Dimchev, A. Nicolas, C.M. Sommer, C. Kreuzinger, C. Dotter, L. Knaus, Z. Dobler, E. Cacci, F.K. Schur, J.G. Danzl, G. Novarino, Nature Communications 12 (2021).","ista":"Morandell J, Schwarz LA, Basilico B, Tasciyan S, Dimchev GA, Nicolas A, Sommer CM, Kreuzinger C, Dotter C, Knaus L, Dobler Z, Cacci E, Schur FK, Danzl JG, Novarino G. 2021. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nature Communications. 12(1), 3058.","ama":"Morandell J, Schwarz LA, Basilico B, et al. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. <i>Nature Communications</i>. 2021;12(1). doi:<a href=\"https://doi.org/10.1038/s41467-021-23123-x\">10.1038/s41467-021-23123-x</a>","mla":"Morandell, Jasmin, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” <i>Nature Communications</i>, vol. 12, no. 1, 3058, Springer Nature, 2021, doi:<a href=\"https://doi.org/10.1038/s41467-021-23123-x\">10.1038/s41467-021-23123-x</a>."},"acknowledgement":"We thank A. Coll Manzano, F. Freeman, M. Ladron de Guevara, and A. Ç. Yahya for technical assistance, S. Deixler, A. Lepold, and A. Schlerka for the management of our animal colony, as well as M. Schunn and the Preclinical Facility team for technical assistance. We thank K. Heesom and her team at the University of Bristol Proteomics Facility for the proteomics sample preparation, data generation, and analysis support. We thank Y. B. Simon for kindly providing the plasmid for lentiviral labeling. Further, we thank M. Sixt for his advice regarding cell migration and the fruitful discussions. This work was supported by the ISTPlus postdoctoral fellowship (Grant Agreement No. 754411) to B.B., by the European Union’s Horizon 2020 research and innovation program (ERC) grant 715508 (REVERSEAUTISM), and by the Austrian Science Fund (FWF) to G.N. (DK W1232-B24 and SFB F7807-B) and to J.G.D (I3600-B27).","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","quality_controlled":"1","oa_version":"Published Version","project":[{"grant_number":"754411","call_identifier":"H2020","_id":"260C2330-B435-11E9-9278-68D0E5697425","name":"ISTplus - Postdoctoral Fellowships"},{"grant_number":"715508","name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models","_id":"25444568-B435-11E9-9278-68D0E5697425","call_identifier":"H2020"},{"grant_number":"W1232-B24","name":"Molecular Drug Targets","_id":"2548AE96-B435-11E9-9278-68D0E5697425","call_identifier":"FWF"},{"_id":"05A0D778-7A3F-11EA-A408-12923DDC885E","name":"Neural stem cells in autism and epilepsy","grant_number":"F07807"},{"name":"Optical control of synaptic function via adhesion molecules","_id":"265CB4D0-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","grant_number":"I03600"}],"_id":"9429","publication_identifier":{"eissn":["2041-1723"]},"oa":1,"volume":12,"date_updated":"2024-09-10T12:04:26Z","article_processing_charge":"No"},{"year":"2020","doi":"10.1016/j.gde.2020.06.004","ec_funded":1,"title":"Molecular mechanisms for targeted ASD treatments","external_id":{"isi":["000598918900019"],"pmid":["32659636"]},"tmp":{"legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","image":"/images/cc_by_nc_nd.png","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","short":"CC BY-NC-ND (4.0)"},"isi":1,"related_material":{"record":[{"relation":"dissertation_contains","id":"8620","status":"public"}]},"ddc":["570"],"publication_status":"published","citation":{"ieee":"B. Basilico, J. Morandell, and G. Novarino, “Molecular mechanisms for targeted ASD treatments,” <i>Current Opinion in Genetics and Development</i>, vol. 65, no. 12. Elsevier, pp. 126–137, 2020.","apa":"Basilico, B., Morandell, J., &#38; Novarino, G. (2020). Molecular mechanisms for targeted ASD treatments. <i>Current Opinion in Genetics and Development</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.gde.2020.06.004\">https://doi.org/10.1016/j.gde.2020.06.004</a>","chicago":"Basilico, Bernadette, Jasmin Morandell, and Gaia Novarino. “Molecular Mechanisms for Targeted ASD Treatments.” <i>Current Opinion in Genetics and Development</i>. Elsevier, 2020. <a href=\"https://doi.org/10.1016/j.gde.2020.06.004\">https://doi.org/10.1016/j.gde.2020.06.004</a>.","ama":"Basilico B, Morandell J, Novarino G. Molecular mechanisms for targeted ASD treatments. <i>Current Opinion in Genetics and Development</i>. 2020;65(12):126-137. doi:<a href=\"https://doi.org/10.1016/j.gde.2020.06.004\">10.1016/j.gde.2020.06.004</a>","mla":"Basilico, Bernadette, et al. “Molecular Mechanisms for Targeted ASD Treatments.” <i>Current Opinion in Genetics and Development</i>, vol. 65, no. 12, Elsevier, 2020, pp. 126–37, doi:<a href=\"https://doi.org/10.1016/j.gde.2020.06.004\">10.1016/j.gde.2020.06.004</a>.","ista":"Basilico B, Morandell J, Novarino G. 2020. Molecular mechanisms for targeted ASD treatments. Current Opinion in Genetics and Development. 65(12), 126–137.","short":"B. Basilico, J. Morandell, G. Novarino, Current Opinion in Genetics and Development 65 (2020) 126–137."},"abstract":[{"text":"The possibility to generate construct valid animal models enabled the development and testing of therapeutic strategies targeting the core features of autism spectrum disorders (ASDs). At the same time, these studies highlighted the necessity of identifying sensitive developmental time windows for successful therapeutic interventions. Animal and human studies also uncovered the possibility to stratify the variety of ASDs in molecularly distinct subgroups, potentially facilitating effective treatment design. Here, we focus on the molecular pathways emerging as commonly affected by mutations in diverse ASD-risk genes, on their role during critical windows of brain development and the potential treatments targeting these biological processes.","lang":"eng"}],"author":[{"last_name":"Basilico","full_name":"Basilico, Bernadette","orcid":"0000-0003-1843-3173","first_name":"Bernadette","id":"36035796-5ACA-11E9-A75E-7AF2E5697425"},{"full_name":"Morandell, Jasmin","last_name":"Morandell","first_name":"Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87"},{"id":"3E57A680-F248-11E8-B48F-1D18A9856A87","first_name":"Gaia","full_name":"Novarino, Gaia","last_name":"Novarino","orcid":"0000-0002-7673-7178"}],"date_updated":"2024-09-10T12:04:25Z","volume":65,"oa":1,"article_processing_charge":"Yes (via OA deal)","_id":"8131","pmid":1,"publication_identifier":{"eissn":["18790380"],"issn":["0959437X"]},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","quality_controlled":"1","oa_version":"Published Version","project":[{"name":"ISTplus - Postdoctoral Fellowships","_id":"260C2330-B435-11E9-9278-68D0E5697425","call_identifier":"H2020","grant_number":"754411"},{"grant_number":"W1232-B24","call_identifier":"FWF","_id":"2548AE96-B435-11E9-9278-68D0E5697425","name":"Molecular Drug Targets"},{"grant_number":"F07807","name":"Neural stem cells in autism and epilepsy","_id":"05A0D778-7A3F-11EA-A408-12923DDC885E"}],"month":"12","article_type":"original","date_published":"2020-12-01T00:00:00Z","publisher":"Elsevier","scopus_import":"1","language":[{"iso":"eng"}],"license":"https://creativecommons.org/licenses/by-nc-nd/4.0/","has_accepted_license":"1","department":[{"_id":"GaNo"}],"file":[{"file_size":1381545,"file_name":"2020_CurrentOpGenetics_Basilico.pdf","date_created":"2020-07-22T06:47:45Z","access_level":"open_access","date_updated":"2020-07-22T06:47:45Z","success":1,"relation":"main_file","content_type":"application/pdf","creator":"dernst","file_id":"8146"}],"date_created":"2020-07-19T22:00:58Z","day":"01","type":"journal_article","intvolume":"        65","status":"public","issue":"12","publication":"Current Opinion in Genetics and Development","file_date_updated":"2020-07-22T06:47:45Z","page":"126-137"},{"date_created":"2020-10-07T14:53:13Z","file":[{"creator":"jmorande","file_id":"8621","content_type":"application/pdf","relation":"main_file","date_created":"2020-10-07T14:41:49Z","checksum":"7ee83e42de3e5ce2fedb44dff472f75f","file_name":"Jasmin_Morandell_Thesis-2020_final.pdf","file_size":16155786,"embargo":"2021-10-15","date_updated":"2021-10-16T22:30:04Z","access_level":"open_access"},{"access_level":"closed","date_updated":"2021-10-16T22:30:04Z","embargo_to":"open_access","checksum":"5e0464af453734210ce7aab7b4a92e3a","date_created":"2020-10-07T14:45:07Z","file_size":24344152,"file_name":"Jasmin_Morandell_Thesis-2020_final.zip","file_id":"8622","creator":"jmorande","relation":"source_file","content_type":"application/x-zip-compressed"}],"department":[{"_id":"GaNo"}],"has_accepted_license":"1","degree_awarded":"PhD","language":[{"iso":"eng"}],"publisher":"Institute of Science and Technology Austria","date_published":"2020-10-12T00:00:00Z","month":"10","file_date_updated":"2021-10-16T22:30:04Z","page":"138","supervisor":[{"id":"3E57A680-F248-11E8-B48F-1D18A9856A87","first_name":"Gaia","last_name":"Novarino","full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178"}],"status":"public","type":"dissertation","day":"12","ddc":["610"],"related_material":{"record":[{"status":"public","relation":"part_of_dissertation","id":"7800"},{"status":"public","id":"8131","relation":"part_of_dissertation"}]},"alternative_title":["ISTA Thesis"],"title":"Illuminating the role of Cul3 in autism spectrum disorder pathogenesis","acknowledged_ssus":[{"_id":"Bio"},{"_id":"PreCl"}],"year":"2020","doi":"10.15479/AT:ISTA:8620","acknowledgement":"I would like to especially thank Armel Nicolas from the Proteomics and Christoph Sommer from the Bioimaging Facilities for the data analysis, and to thank the team of the Preclinical Facility, especially Sabina Deixler, Angela Schlerka, Anita Lepold, Mihalea Mihai and Michael Schun for taking care of the mouse line maintenance and their great support.","user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","oa_version":"Published Version","project":[{"call_identifier":"FWF","name":"Molecular Drug Targets","_id":"2548AE96-B435-11E9-9278-68D0E5697425","grant_number":"W1232-B24"},{"name":"Neural stem cells in autism and epilepsy","_id":"05A0D778-7A3F-11EA-A408-12923DDC885E","grant_number":"F07807"}],"_id":"8620","publication_identifier":{"issn":["2663-337X"]},"oa":1,"date_updated":"2024-09-10T12:04:25Z","article_processing_charge":"No","author":[{"last_name":"Morandell","full_name":"Morandell, Jasmin","first_name":"Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87"}],"abstract":[{"text":"The development of the human brain occurs through a tightly regulated series of dynamic and adaptive processes during prenatal and postnatal life. A disruption of this strictly orchestrated series of events can lead to a number of neurodevelopmental conditions, including Autism Spectrum Disorders (ASDs). ASDs are a very common, etiologically and phenotypically heterogeneous group of disorders sharing the core symptoms of social interaction and communication deficits and restrictive and repetitive interests and behaviors. They are estimated to affect one in 59 individuals in the U.S. and, over the last three decades, mutations in more than a hundred genetic loci have been convincingly linked to ASD pathogenesis. Yet, for the vast majority of these ASD-risk genes their role during brain development and precise molecular function still remain elusive.\r\nDe novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin 3 (CUL3) lead to ASD. In the study described here, we used Cul3 mouse models to evaluate the consequences of Cul3 mutations in vivo. Our results show that Cul3 heterozygous knockout mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. Cul3+/-, Cul3+/fl Emx1-Cre and Cul3fl/fl Emx1-Cre mutant brains display cortical lamination abnormalities due to defective migration of post-mitotic excitatory neurons, as well as reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal cortical organization, Cul3 heterozygous deletion is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level we show that Cul3 regulates cytoskeletal and adhesion protein abundance in the mouse embryonic cortex. Abnormal regulation of cytoskeletal proteins in Cul3 mutant neural cells results in atypical organization of the actin mesh at the cell leading edge. Of note, heterozygous deletion of Cul3 in adult mice does not induce the majority of the behavioral defects observed in constitutive Cul3 haploinsufficient animals, pointing to a critical time-window for Cul3 deficiency.\r\nIn conclusion, our data indicate that Cul3 plays a critical role in the regulation of cytoskeletal proteins and neuronal migration. ASD-associated defects and behavioral abnormalities are primarily due to dosage sensitive Cul3 functions at early brain developmental stages.","lang":"eng"}],"publication_status":"published","citation":{"chicago":"Morandell, Jasmin. “Illuminating the Role of Cul3 in Autism Spectrum Disorder Pathogenesis.” Institute of Science and Technology Austria, 2020. <a href=\"https://doi.org/10.15479/AT:ISTA:8620\">https://doi.org/10.15479/AT:ISTA:8620</a>.","ieee":"J. Morandell, “Illuminating the role of Cul3 in autism spectrum disorder pathogenesis,” Institute of Science and Technology Austria, 2020.","apa":"Morandell, J. (2020). <i>Illuminating the role of Cul3 in autism spectrum disorder pathogenesis</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/AT:ISTA:8620\">https://doi.org/10.15479/AT:ISTA:8620</a>","ista":"Morandell J. 2020. Illuminating the role of Cul3 in autism spectrum disorder pathogenesis. Institute of Science and Technology Austria.","short":"J. Morandell, Illuminating the Role of Cul3 in Autism Spectrum Disorder Pathogenesis, Institute of Science and Technology Austria, 2020.","mla":"Morandell, Jasmin. <i>Illuminating the Role of Cul3 in Autism Spectrum Disorder Pathogenesis</i>. Institute of Science and Technology Austria, 2020, doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8620\">10.15479/AT:ISTA:8620</a>.","ama":"Morandell J. Illuminating the role of Cul3 in autism spectrum disorder pathogenesis. 2020. doi:<a href=\"https://doi.org/10.15479/AT:ISTA:8620\">10.15479/AT:ISTA:8620</a>"}}]