[{"title":"The metabolism of the developing brain : How large neutral amino acids modulate perinatal neuronal excitability and survival","degree_awarded":"PhD","author":[{"first_name":"Lisa","last_name":"Knaus","id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87","full_name":"Knaus, Lisa"}],"file":[{"date_created":"2023-06-01T13:48:41Z","access_level":"closed","file_id":"13112","date_updated":"2023-06-01T13:48:41Z","checksum":"4b69a4ac0bbf4163d59c0b58dcb4f2c3","file_size":12991551,"relation":"source_file","content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","creator":"lknaus","file_name":"Thesis_Lisa Knaus_approved_final.docx"},{"creator":"lknaus","relation":"main_file","content_type":"application/pdf","file_size":9309015,"file_name":"Thesis_Lisa Knaus_approved_final_pdfa2b.pdf","access_level":"open_access","date_created":"2023-06-02T09:47:29Z","checksum":"6903d152aa01181d87a696085af31c83","date_updated":"2023-06-07T08:41:49Z","file_id":"13114"}],"day":"31","article_processing_charge":"No","ec_funded":1,"publisher":"Institute of Science and Technology Austria","user_id":"8b945eb4-e2f2-11eb-945a-df72226e66a9","department":[{"_id":"GradSch"},{"_id":"GaNo"}],"doi":"10.15479/at:ista:13107","publication_identifier":{"issn":["2663 - 337X"]},"language":[{"iso":"eng"}],"project":[{"call_identifier":"H2020","_id":"25444568-B435-11E9-9278-68D0E5697425","name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models","grant_number":"715508"},{"grant_number":"W1232-B24","name":"Molecular Drug Targets","call_identifier":"FWF","_id":"2548AE96-B435-11E9-9278-68D0E5697425"}],"file_date_updated":"2023-06-07T08:41:49Z","date_created":"2023-06-01T09:05:24Z","page":"147","date_updated":"2024-02-07T08:03:33Z","abstract":[{"text":"Within the human body, the brain exhibits the highest rate of energy consumption amongst all organs, with the majority of generated ATP being utilized to sustain neuronal activity. Therefore, the metabolism of the mature cerebral cortex is geared towards preserving metabolic homeostasis whilst generating significant amounts of energy. This requires a precise interplay between diverse metabolic pathways, spanning from a tissue-wide scale to the level of individual neurons. Disturbances to this delicate metabolic equilibrium, such as those resulting from maternal malnutrition\r\nor mutations affecting metabolic enzymes, often result in neuropathological variants of neurodevelopment. For instance, mutations in SLC7A5, a transporter of metabolically essential large neutral amino acids (LNAAs), have been associated with autism and microcephaly. However, despite recent progress in the field, the extent of metabolic restructuring that occurs within the developing brain and the corresponding alterations in nutrient demands during various critical periods remain largely unknown. To investigate this, we performed metabolomic profiling of the murine cerebral cortex to characterize the metabolic state of the forebrain at different developmental stages. We found that the developing cortex undergoes substantial metabolic reprogramming, with specific sets of metabolites displaying stage-specific changes. According to our observations, we determined a distinct temporal period in postnatal development during which the cortex displays heightened reliance on LNAAs. Hence, using a conditional knock-out mouse model, we deleted Slc7a5 in neural cells, allowing us to monitor the impact of a perturbed neuronal metabolic state across multiple developmental stages of corticogenesis. We found that manipulating the levels of essential LNAAs in cortical neurons in vivo affects one particular perinatal developmental period critical for cortical network refinement. Abnormally low intracellular LNAA levels result in cell-autonomous alterations in neuronal lipid metabolism, excitability, and survival during this particular time window. Although most of the effects of Slc7a5 deletion on neuronal physiology are transient, derailment of these processes during this brief but crucial window leads to long-term circuit dysfunction in mice. In conclusion, out data indicate that the cerebral cortex undergoes significant metabolic reorganization during development. This process involves the intricate integration of multiple metabolic pathways to ensure optimal neuronal function throughout different developmental stages. Our findings offer a paradigm for understanding how neurons synchronize the expression of nutrient-related genes with their activity to allow proper brain maturation. Further, our results demonstrate that disruptions in these precisely calibrated metabolic processes during critical periods of brain development may result in neuropathological outcomes in mice and in humans.","lang":"eng"}],"type":"dissertation","oa_version":"Published Version","month":"05","_id":"13107","year":"2023","supervisor":[{"first_name":"Gaia","last_name":"Novarino","full_name":"Novarino, Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-7673-7178"}],"ddc":["570"],"date_published":"2023-05-31T00:00:00Z","acknowledged_ssus":[{"_id":"PreCl"},{"_id":"Bio"},{"_id":"EM-Fac"}],"oa":1,"publication_status":"published","has_accepted_license":"1","related_material":{"record":[{"status":"public","id":"12802","relation":"part_of_dissertation"}]},"citation":{"ama":"Knaus L. The metabolism of the developing brain : How large neutral amino acids modulate perinatal neuronal excitability and survival. 2023. doi:<a href=\"https://doi.org/10.15479/at:ista:13107\">10.15479/at:ista:13107</a>","ista":"Knaus L. 2023. The metabolism of the developing brain : How large neutral amino acids modulate perinatal neuronal excitability and survival. Institute of Science and Technology Austria.","mla":"Knaus, Lisa. <i>The Metabolism of the Developing Brain : How Large Neutral Amino Acids Modulate Perinatal Neuronal Excitability and Survival</i>. Institute of Science and Technology Austria, 2023, doi:<a href=\"https://doi.org/10.15479/at:ista:13107\">10.15479/at:ista:13107</a>.","apa":"Knaus, L. (2023). <i>The metabolism of the developing brain : How large neutral amino acids modulate perinatal neuronal excitability and survival</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/at:ista:13107\">https://doi.org/10.15479/at:ista:13107</a>","ieee":"L. Knaus, “The metabolism of the developing brain : How large neutral amino acids modulate perinatal neuronal excitability and survival,” Institute of Science and Technology Austria, 2023.","chicago":"Knaus, Lisa. “The Metabolism of the Developing Brain : How Large Neutral Amino Acids Modulate Perinatal Neuronal Excitability and Survival.” Institute of Science and Technology Austria, 2023. <a href=\"https://doi.org/10.15479/at:ista:13107\">https://doi.org/10.15479/at:ista:13107</a>.","short":"L. Knaus, The Metabolism of the Developing Brain : How Large Neutral Amino Acids Modulate Perinatal Neuronal Excitability and Survival, Institute of Science and Technology Austria, 2023."},"alternative_title":["ISTA Thesis"],"status":"public"},{"doi":"10.1016/j.cell.2023.02.037","quality_controlled":"1","publication_identifier":{"issn":["0092-8674"]},"keyword":["General Biochemistry","Genetics and Molecular Biology"],"isi":1,"issue":"9","language":[{"iso":"eng"}],"project":[{"grant_number":"W1232-B24","_id":"2548AE96-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","name":"Molecular Drug Targets"},{"grant_number":"725780","name":"Principles of Neural Stem Cell Lineage Progression in Cerebral Cortex Development","call_identifier":"H2020","_id":"260018B0-B435-11E9-9278-68D0E5697425"},{"_id":"25444568-B435-11E9-9278-68D0E5697425","call_identifier":"H2020","name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models","grant_number":"715508"}],"title":"Large neutral amino acid levels tune perinatal neuronal excitability and survival","author":[{"id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87","full_name":"Knaus, Lisa","first_name":"Lisa","last_name":"Knaus"},{"first_name":"Bernadette","last_name":"Basilico","full_name":"Basilico, Bernadette","id":"36035796-5ACA-11E9-A75E-7AF2E5697425","orcid":"0000-0003-1843-3173"},{"full_name":"Malzl, Daniel","last_name":"Malzl","first_name":"Daniel"},{"last_name":"Gerykova Bujalkova","first_name":"Maria","full_name":"Gerykova Bujalkova, Maria"},{"full_name":"Smogavec, Mateja","last_name":"Smogavec","first_name":"Mateja"},{"last_name":"Schwarz","first_name":"Lena A.","full_name":"Schwarz, Lena A."},{"full_name":"Gorkiewicz, Sarah","id":"f141a35d-15a9-11ec-9fb2-fef6becc7b6f","last_name":"Gorkiewicz","first_name":"Sarah"},{"id":"4CD6AAC6-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-3183-8207","full_name":"Amberg, Nicole","first_name":"Nicole","last_name":"Amberg"},{"full_name":"Pauler, Florian","orcid":"0000-0002-7462-0048","id":"48EA0138-F248-11E8-B48F-1D18A9856A87","first_name":"Florian","last_name":"Pauler"},{"full_name":"Knittl-Frank, Christian","first_name":"Christian","last_name":"Knittl-Frank"},{"full_name":"Tassinari, Marianna","id":"7af593f1-d44a-11ed-bf94-a3646a6bb35e","first_name":"Marianna","last_name":"Tassinari"},{"full_name":"Maulide, Nuno","first_name":"Nuno","last_name":"Maulide"},{"full_name":"Rülicke, Thomas","last_name":"Rülicke","first_name":"Thomas"},{"full_name":"Menche, Jörg","last_name":"Menche","first_name":"Jörg"},{"first_name":"Simon","last_name":"Hippenmeyer","id":"37B36620-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-2279-1061","full_name":"Hippenmeyer, Simon"},{"first_name":"Gaia","last_name":"Novarino","full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178","id":"3E57A680-F248-11E8-B48F-1D18A9856A87"}],"day":"27","file":[{"access_level":"open_access","date_created":"2023-05-02T09:26:21Z","checksum":"47e94fbe19e86505b429cb7a5b503ce6","file_id":"12889","date_updated":"2023-05-02T09:26:21Z","creator":"dernst","file_size":15712841,"relation":"main_file","content_type":"application/pdf","file_name":"2023_Cell_Knaus.pdf","success":1}],"publication":"Cell","article_type":"original","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"ec_funded":1,"scopus_import":"1","article_processing_charge":"Yes (via OA deal)","publisher":"Elsevier","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","department":[{"_id":"SiHi"},{"_id":"GaNo"}],"ddc":["570"],"date_published":"2023-04-27T00:00:00Z","acknowledged_ssus":[{"_id":"PreCl"},{"_id":"EM-Fac"},{"_id":"Bio"},{"_id":"LifeSc"}],"oa":1,"publication_status":"published","has_accepted_license":"1","related_material":{"record":[{"id":"13107","status":"public","relation":"dissertation_contains"}],"link":[{"relation":"press_release","url":"https://ista.ac.at/en/news/feed-them-or-lose-them/","description":"News on ISTA Website"}]},"intvolume":"       186","citation":{"mla":"Knaus, Lisa, et al. “Large Neutral Amino Acid Levels Tune Perinatal Neuronal Excitability and Survival.” <i>Cell</i>, vol. 186, no. 9, Elsevier, 2023, p. 1950–1967.e25, doi:<a href=\"https://doi.org/10.1016/j.cell.2023.02.037\">10.1016/j.cell.2023.02.037</a>.","ista":"Knaus L, Basilico B, Malzl D, Gerykova Bujalkova M, Smogavec M, Schwarz LA, Gorkiewicz S, Amberg N, Pauler F, Knittl-Frank C, Tassinari M, Maulide N, Rülicke T, Menche J, Hippenmeyer S, Novarino G. 2023. Large neutral amino acid levels tune perinatal neuronal excitability and survival. Cell. 186(9), 1950–1967.e25.","apa":"Knaus, L., Basilico, B., Malzl, D., Gerykova Bujalkova, M., Smogavec, M., Schwarz, L. A., … Novarino, G. (2023). Large neutral amino acid levels tune perinatal neuronal excitability and survival. <i>Cell</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.cell.2023.02.037\">https://doi.org/10.1016/j.cell.2023.02.037</a>","ama":"Knaus L, Basilico B, Malzl D, et al. Large neutral amino acid levels tune perinatal neuronal excitability and survival. <i>Cell</i>. 2023;186(9):1950-1967.e25. doi:<a href=\"https://doi.org/10.1016/j.cell.2023.02.037\">10.1016/j.cell.2023.02.037</a>","short":"L. Knaus, B. Basilico, D. Malzl, M. Gerykova Bujalkova, M. Smogavec, L.A. Schwarz, S. Gorkiewicz, N. Amberg, F. Pauler, C. Knittl-Frank, M. Tassinari, N. Maulide, T. Rülicke, J. Menche, S. Hippenmeyer, G. Novarino, Cell 186 (2023) 1950–1967.e25.","ieee":"L. Knaus <i>et al.</i>, “Large neutral amino acid levels tune perinatal neuronal excitability and survival,” <i>Cell</i>, vol. 186, no. 9. Elsevier, p. 1950–1967.e25, 2023.","chicago":"Knaus, Lisa, Bernadette Basilico, Daniel Malzl, Maria Gerykova Bujalkova, Mateja Smogavec, Lena A. Schwarz, Sarah Gorkiewicz, et al. “Large Neutral Amino Acid Levels Tune Perinatal Neuronal Excitability and Survival.” <i>Cell</i>. Elsevier, 2023. <a href=\"https://doi.org/10.1016/j.cell.2023.02.037\">https://doi.org/10.1016/j.cell.2023.02.037</a>."},"status":"public","external_id":{"isi":["000991468700001"]},"volume":186,"date_created":"2023-04-05T08:15:40Z","file_date_updated":"2023-05-02T09:26:21Z","page":"1950-1967.e25","oa_version":"Published Version","month":"04","type":"journal_article","abstract":[{"lang":"eng","text":"Little is known about the critical metabolic changes that neural cells have to undergo during development and how temporary shifts in this program can influence brain circuitries and behavior. Inspired by the discovery that mutations in SLC7A5, a transporter of metabolically essential large neutral amino acids (LNAAs), lead to autism, we employed metabolomic profiling to study the metabolic states of the cerebral cortex across different developmental stages. We found that the forebrain undergoes significant metabolic remodeling throughout development, with certain groups of metabolites showing stage-specific changes, but what are the consequences of perturbing this metabolic program? By manipulating Slc7a5 expression in neural cells, we found that the metabolism of LNAAs and lipids are interconnected in the cortex. Deletion of Slc7a5 in neurons affects the postnatal metabolic state, leading to a shift in lipid metabolism. Additionally, it causes stage- and cell-type-specific alterations in neuronal activity patterns, resulting in a long-term circuit dysfunction."}],"date_updated":"2024-02-07T08:03:32Z","_id":"12802","acknowledgement":"We thank A. Freeman and V. Voronin for technical assistance, S. Deixler, A. Stichelberger, M. Schunn, and the Preclinical Facility for managing our animal colony. We thank L. Andersen and J. Sonntag, who were involved in generating the MADM lines. We thank the ISTA LSF Mass Spectrometry Core Facility for assistance with the proteomic analysis, as well as the ISTA electron microscopy and Imaging and Optics facility for technical support. Metabolomics LC-MS/MS analysis was performed by the Metabolomics Facility at Vienna BioCenter Core Facilities (VBCF). We acknowledge the support of the EMBL Metabolomics Core Facility (MCF) for lipidomics and intracellular metabolomics mass spectrometry data acquisition and analysis. RNA sequencing was performed by the Next Generation Sequencing Facility at VBCF. Schematics were generated using Biorender.com. This work was supported by the Austrian Science Fund (FWF, DK W1232-B24) and by the European Union’s Horizon 2020 research and innovation program (ERC) grant 725780 (LinPro) to S.H. and 715508 (REVERSEAUTISM) to G.N.","year":"2023"},{"publication_status":"published","oa":1,"has_accepted_license":"1","date_published":"2021-05-24T00:00:00Z","ddc":["572"],"acknowledged_ssus":[{"_id":"PreCl"}],"status":"public","external_id":{"isi":["000658769900010"]},"related_material":{"record":[{"relation":"earlier_version","status":"public","id":"7800"},{"id":"12401","status":"public","relation":"dissertation_contains"}],"link":[{"relation":"press_release","url":"https://ist.ac.at/en/news/defective-gene-slows-down-brain-cells/"}]},"intvolume":"        12","citation":{"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>","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>.","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>","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).","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."},"type":"journal_article","month":"05","oa_version":"Published Version","date_updated":"2024-09-10T12:04:26Z","abstract":[{"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.","lang":"eng"}],"volume":12,"file_date_updated":"2021-05-28T12:39:43Z","date_created":"2021-05-28T11:49:46Z","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).","year":"2021","_id":"9429","publication_identifier":{"eissn":["2041-1723"]},"doi":"10.1038/s41467-021-23123-x","quality_controlled":"1","project":[{"name":"ISTplus - Postdoctoral Fellowships","call_identifier":"H2020","_id":"260C2330-B435-11E9-9278-68D0E5697425","grant_number":"754411"},{"name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models","call_identifier":"H2020","_id":"25444568-B435-11E9-9278-68D0E5697425","grant_number":"715508"},{"grant_number":"W1232-B24","name":"Molecular Drug Targets","call_identifier":"FWF","_id":"2548AE96-B435-11E9-9278-68D0E5697425"},{"_id":"05A0D778-7A3F-11EA-A408-12923DDC885E","name":"Neural stem cells in autism and epilepsy","grant_number":"F07807"},{"_id":"265CB4D0-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","name":"Optical control of synaptic function via adhesion molecules","grant_number":"I03600"}],"keyword":["General Biochemistry","Genetics and Molecular Biology"],"isi":1,"issue":"1","language":[{"iso":"eng"}],"author":[{"full_name":"Morandell, Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87","first_name":"Jasmin","last_name":"Morandell"},{"id":"29A8453C-F248-11E8-B48F-1D18A9856A87","full_name":"Schwarz, Lena A","last_name":"Schwarz","first_name":"Lena A"},{"id":"36035796-5ACA-11E9-A75E-7AF2E5697425","orcid":"0000-0003-1843-3173","full_name":"Basilico, Bernadette","first_name":"Bernadette","last_name":"Basilico"},{"id":"4323B49C-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-1671-393X","full_name":"Tasciyan, Saren","last_name":"Tasciyan","first_name":"Saren"},{"full_name":"Dimchev, Georgi A","orcid":"0000-0001-8370-6161","id":"38C393BE-F248-11E8-B48F-1D18A9856A87","first_name":"Georgi A","last_name":"Dimchev"},{"full_name":"Nicolas, Armel","id":"2A103192-F248-11E8-B48F-1D18A9856A87","first_name":"Armel","last_name":"Nicolas"},{"last_name":"Sommer","first_name":"Christoph M","full_name":"Sommer, Christoph M","orcid":"0000-0003-1216-9105","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Kreuzinger","first_name":"Caroline","full_name":"Kreuzinger, Caroline","id":"382077BA-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Dotter, Christoph","orcid":"0000-0002-9033-9096","id":"4C66542E-F248-11E8-B48F-1D18A9856A87","first_name":"Christoph","last_name":"Dotter"},{"full_name":"Knaus, Lisa","id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87","first_name":"Lisa","last_name":"Knaus"},{"last_name":"Dobler","first_name":"Zoe","id":"D23090A2-9057-11EA-883A-A8396FC7A38F","full_name":"Dobler, Zoe"},{"full_name":"Cacci, Emanuele","first_name":"Emanuele","last_name":"Cacci"},{"full_name":"Schur, Florian KM","orcid":"0000-0003-4790-8078","id":"48AD8942-F248-11E8-B48F-1D18A9856A87","last_name":"Schur","first_name":"Florian KM"},{"first_name":"Johann G","last_name":"Danzl","orcid":"0000-0001-8559-3973","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","full_name":"Danzl, Johann G"},{"id":"3E57A680-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-7673-7178","full_name":"Novarino, Gaia","first_name":"Gaia","last_name":"Novarino"}],"day":"24","file":[{"access_level":"open_access","date_created":"2021-05-28T12:39:43Z","checksum":"337e0f7959c35ec959984cacdcb472ba","file_id":"9430","date_updated":"2021-05-28T12:39:43Z","creator":"kschuh","file_size":9358599,"content_type":"application/pdf","relation":"main_file","file_name":"2021_NatureCommunications_Morandell.pdf","success":1}],"article_number":"3058","title":"Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development","publisher":"Springer Nature","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","department":[{"_id":"GaNo"},{"_id":"JoDa"},{"_id":"FlSc"},{"_id":"MiSi"},{"_id":"LifeSc"},{"_id":"Bio"}],"publication":"Nature Communications","article_type":"original","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"article_processing_charge":"No","ec_funded":1},{"isi":1,"language":[{"iso":"eng"}],"issue":"11","project":[{"_id":"25444568-B435-11E9-9278-68D0E5697425","call_identifier":"H2020","name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models","grant_number":"715508"},{"grant_number":"W1232-B24","name":"Molecular Drug Targets","_id":"2548AE96-B435-11E9-9278-68D0E5697425","call_identifier":"FWF"}],"doi":"10.3390/genes12111746","quality_controlled":"1","publication_identifier":{"eissn":["2073-4425"]},"publication":"Genes","ec_funded":1,"scopus_import":"1","article_processing_charge":"No","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"article_type":"original","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","publisher":"MDPI","department":[{"_id":"GaNo"}],"title":"Translating the role of mtor-and ras-associated signalopathies in autism spectrum disorder: Models, mechanisms and treatment","article_number":"1746","author":[{"first_name":"Verica","last_name":"Vasic","full_name":"Vasic, Verica"},{"first_name":"Mattson S.O.","last_name":"Jones","full_name":"Jones, Mattson S.O."},{"first_name":"Denise","last_name":"Haslinger","id":"76922BDA-3D3B-11EA-90BD-A44F3DDC885E","full_name":"Haslinger, Denise"},{"first_name":"Lisa","last_name":"Knaus","id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87","full_name":"Knaus, Lisa"},{"last_name":"Schmeisser","first_name":"Michael J.","full_name":"Schmeisser, Michael J."},{"full_name":"Novarino, Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-7673-7178","first_name":"Gaia","last_name":"Novarino"},{"full_name":"Chiocchetti, Andreas G.","first_name":"Andreas G.","last_name":"Chiocchetti"}],"day":"30","file":[{"date_created":"2022-05-16T07:02:27Z","access_level":"open_access","date_updated":"2022-05-16T07:02:27Z","file_id":"11380","checksum":"256cb832a9c3051c7dc741f6423b8cbd","content_type":"application/pdf","relation":"main_file","file_size":1335308,"creator":"dernst","success":1,"file_name":"2021_Genes_Vasic.pdf"}],"intvolume":"        12","citation":{"short":"V. Vasic, M.S.O. Jones, D. Haslinger, L. Knaus, M.J. Schmeisser, G. Novarino, A.G. Chiocchetti, Genes 12 (2021).","ieee":"V. Vasic <i>et al.</i>, “Translating the role of mtor-and ras-associated signalopathies in autism spectrum disorder: Models, mechanisms and treatment,” <i>Genes</i>, vol. 12, no. 11. MDPI, 2021.","chicago":"Vasic, Verica, Mattson S.O. Jones, Denise Haslinger, Lisa Knaus, Michael J. Schmeisser, Gaia Novarino, and Andreas G. Chiocchetti. “Translating the Role of Mtor-and Ras-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment.” <i>Genes</i>. MDPI, 2021. <a href=\"https://doi.org/10.3390/genes12111746\">https://doi.org/10.3390/genes12111746</a>.","ista":"Vasic V, Jones MSO, Haslinger D, Knaus L, Schmeisser MJ, Novarino G, Chiocchetti AG. 2021. Translating the role of mtor-and ras-associated signalopathies in autism spectrum disorder: Models, mechanisms and treatment. Genes. 12(11), 1746.","mla":"Vasic, Verica, et al. “Translating the Role of Mtor-and Ras-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment.” <i>Genes</i>, vol. 12, no. 11, 1746, MDPI, 2021, doi:<a href=\"https://doi.org/10.3390/genes12111746\">10.3390/genes12111746</a>.","apa":"Vasic, V., Jones, M. S. O., Haslinger, D., Knaus, L., Schmeisser, M. J., Novarino, G., &#38; Chiocchetti, A. G. (2021). Translating the role of mtor-and ras-associated signalopathies in autism spectrum disorder: Models, mechanisms and treatment. <i>Genes</i>. MDPI. <a href=\"https://doi.org/10.3390/genes12111746\">https://doi.org/10.3390/genes12111746</a>","ama":"Vasic V, Jones MSO, Haslinger D, et al. Translating the role of mtor-and ras-associated signalopathies in autism spectrum disorder: Models, mechanisms and treatment. <i>Genes</i>. 2021;12(11). doi:<a href=\"https://doi.org/10.3390/genes12111746\">10.3390/genes12111746</a>"},"alternative_title":["Special Issue \"From Genes to Therapy in Autism Spectrum Disorder\""],"status":"public","external_id":{"isi":["000834044200002"]},"date_published":"2021-10-30T00:00:00Z","ddc":["570"],"oa":1,"publication_status":"published","has_accepted_license":"1","_id":"10281","acknowledgement":"This review was funded by the IMI2 Initiative under the grant AIMS-2-TRIALS No 777394, by the Hessian Ministry for Science and Arts; State of Hesse Ministry for Science and Arts: LOEWE-Grant to the CePTER-Consortium (www.uni-frankfurt.de/67689811); Research (BMBF) under the grant RAISE-genic No 779282 all to AGC. This work was also supported by the European Union’s Horizon 2020 research and innovation program (ERC) grant 715508 (REVERSEAUTISM) and by the Austrian Science Fund (FWF) (DK W1232-B24) both to G.N. and both BMBF GeNeRARe 01GM1519A and CRC 1080, project B10, of the German Research Foundation (DFG) to M.J.S, respectively. We want to thank R. Waltes for her support in preparing this manuscript.","year":"2021","volume":12,"date_created":"2021-11-14T23:01:24Z","file_date_updated":"2022-05-16T07:02:27Z","date_updated":"2023-08-14T11:46:12Z","abstract":[{"text":"Mutations affecting mTOR or RAS signaling underlie defined syndromes (the so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder (ASD). These syndromes show a broad variety of somatic phenotypes including cancers, skin abnormalities, heart disease and facial dysmorphisms. Less well studied are the neuropsychiatric symptoms such as ASD. Here, we assess the relevance of these signalopathies in ASD reviewing genetic, human cell model, rodent studies and clinical trials. We conclude that signalopathies have an increased liability for ASD and that, in particular, ASD individuals with dysmorphic features and intellectual disability (ID) have a higher chance for disruptive mutations in RAS- and mTOR-related genes. Studies on rodent and human cell models confirm aberrant neuronal development as the underlying pathology. Human studies further suggest that multiple hits are necessary to induce the respective phenotypes. Recent clinical trials do only report improvements for comorbid conditions such as epilepsy or cancer but not for behavioral aspects. Animal models show that treatment during early development can rescue behavioral phenotypes. Taken together, we suggest investigating the differential roles of mTOR and RAS signaling in both human and rodent models, and to test drug treatment both during and after neuronal development in the available model systems","lang":"eng"}],"oa_version":"Published Version","month":"10","type":"journal_article"},{"language":[{"iso":"eng"}],"project":[{"grant_number":"I03600","_id":"265CB4D0-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","name":"Optical control of synaptic function via adhesion molecules"},{"grant_number":"W1232-B24","call_identifier":"FWF","_id":"2548AE96-B435-11E9-9278-68D0E5697425","name":"Molecular Drug Targets"}],"doi":"10.1101/2020.01.10.902064 ","article_processing_charge":"No","tmp":{"name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","short":"CC BY-NC-ND (4.0)","image":"/images/cc_by_nc_nd.png","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode"},"publication":"bioRxiv","department":[{"_id":"JoDa"},{"_id":"GaNo"},{"_id":"LifeSc"}],"publisher":"Cold Spring Harbor Laboratory","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","title":"Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development","license":"https://creativecommons.org/licenses/by-nc-nd/4.0/","day":"11","file":[{"checksum":"c6799ab5daba80efe8e2ed63c15f8c81","date_updated":"2020-07-14T12:48:03Z","file_id":"7801","access_level":"open_access","date_created":"2020-05-05T14:31:19Z","file_name":"2020.01.10.902064v1.full.pdf","creator":"rsix","relation":"main_file","content_type":"application/pdf","file_size":2931370}],"author":[{"full_name":"Morandell, Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87","last_name":"Morandell","first_name":"Jasmin"},{"full_name":"Schwarz, Lena A","id":"29A8453C-F248-11E8-B48F-1D18A9856A87","first_name":"Lena A","last_name":"Schwarz"},{"full_name":"Basilico, Bernadette","orcid":"0000-0003-1843-3173","id":"36035796-5ACA-11E9-A75E-7AF2E5697425","first_name":"Bernadette","last_name":"Basilico"},{"first_name":"Saren","last_name":"Tasciyan","full_name":"Tasciyan, Saren","orcid":"0000-0003-1671-393X","id":"4323B49C-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Nicolas, Armel","id":"2A103192-F248-11E8-B48F-1D18A9856A87","first_name":"Armel","last_name":"Nicolas"},{"first_name":"Christoph M","last_name":"Sommer","full_name":"Sommer, Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-1216-9105"},{"first_name":"Caroline","last_name":"Kreuzinger","full_name":"Kreuzinger, Caroline","id":"382077BA-F248-11E8-B48F-1D18A9856A87"},{"id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87","full_name":"Knaus, Lisa","first_name":"Lisa","last_name":"Knaus"},{"first_name":"Zoe","last_name":"Dobler","full_name":"Dobler, Zoe","id":"D23090A2-9057-11EA-883A-A8396FC7A38F"},{"last_name":"Cacci","first_name":"Emanuele","full_name":"Cacci, Emanuele"},{"last_name":"Danzl","first_name":"Johann G","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-8559-3973","full_name":"Danzl, Johann G"},{"full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","first_name":"Gaia","last_name":"Novarino"}],"citation":{"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>bioRxiv</i>. doi:<a href=\"https://doi.org/10.1101/2020.01.10.902064 \">10.1101/2020.01.10.902064 </a>","ista":"Morandell J, Schwarz LA, Basilico B, Tasciyan S, Nicolas A, Sommer CM, Kreuzinger C, Knaus L, Dobler Z, Cacci E, Danzl JG, Novarino G. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. bioRxiv, <a href=\"https://doi.org/10.1101/2020.01.10.902064 \">10.1101/2020.01.10.902064 </a>.","mla":"Morandell, Jasmin, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” <i>BioRxiv</i>, Cold Spring Harbor Laboratory, doi:<a href=\"https://doi.org/10.1101/2020.01.10.902064 \">10.1101/2020.01.10.902064 </a>.","apa":"Morandell, J., Schwarz, L. A., Basilico, B., Tasciyan, S., Nicolas, A., Sommer, C. M., … Novarino, G. (n.d.). Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. <i>bioRxiv</i>. Cold Spring Harbor Laboratory. <a href=\"https://doi.org/10.1101/2020.01.10.902064 \">https://doi.org/10.1101/2020.01.10.902064 </a>","ieee":"J. Morandell <i>et al.</i>, “Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development,” <i>bioRxiv</i>. Cold Spring Harbor Laboratory.","chicago":"Morandell, Jasmin, Lena A Schwarz, Bernadette Basilico, Saren Tasciyan, Armel Nicolas, Christoph M Sommer, Caroline Kreuzinger, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” <i>BioRxiv</i>. Cold Spring Harbor Laboratory, n.d. <a href=\"https://doi.org/10.1101/2020.01.10.902064 \">https://doi.org/10.1101/2020.01.10.902064 </a>.","short":"J. Morandell, L.A. Schwarz, B. Basilico, S. Tasciyan, A. Nicolas, C.M. Sommer, C. Kreuzinger, L. Knaus, Z. Dobler, E. Cacci, J.G. Danzl, G. Novarino, BioRxiv (n.d.)."},"related_material":{"record":[{"relation":"dissertation_contains","status":"public","id":"8620"},{"status":"public","id":"9429","relation":"later_version"}]},"status":"public","acknowledged_ssus":[{"_id":"PreCl"}],"date_published":"2020-01-11T00:00:00Z","ddc":["570"],"has_accepted_license":"1","oa":1,"publication_status":"submitted","_id":"7800","year":"2020","date_created":"2020-05-05T14:31:33Z","file_date_updated":"2020-07-14T12:48:03Z","abstract":[{"lang":"eng","text":"De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 (CUL3) lead to autism spectrum disorder (ASD). Here, we used Cul3 mouse models to evaluate the consequences of Cul3 mutations in vivo. Our results show that Cul3 haploinsufficient mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. Cul3 mutant brain displays cortical lamination abnormalities due to defective neuronal migration and reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal columnar organization, Cul3 haploinsufficiency is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level, employing a quantitative proteomic approach, we show that Cul3 regulates cytoskeletal and adhesion protein abundance in mouse embryos. Abnormal regulation of cytoskeletal proteins in Cul3 mutant neuronal cells results in atypical organization of the actin mesh at the cell leading edge, likely causing the observed migration deficits. In contrast to these important functions early in development, Cul3 deficiency appears less relevant at adult stages. In fact, induction of Cul3 haploinsufficiency in adult mice does not result in the behavioral defects observed in constitutive Cul3 haploinsufficient animals. Taken together, our data indicate that Cul3 has a critical role in the regulation of cytoskeletal proteins and neuronal migration and that ASD-associated defects and behavioral abnormalities are primarily due to Cul3 functions at early developmental stages."}],"date_updated":"2024-09-10T12:04:26Z","month":"01","type":"preprint","oa_version":"Preprint"},{"quality_controlled":"1","doi":"10.1016/j.euroneuro.2019.09.039","date_published":"2019-12-13T00:00:00Z","publication_status":"published","publication_identifier":{"issn":["0924-977X"]},"citation":{"chicago":"Knaus, Lisa, Dora-Clara Tarlungeanu, and Gaia Novarino. “S.16.03 A Homozygous Missense Mutation in SLC7A5 Leads to Autism Spectrum Disorder and Microcephaly.” <i>European Neuropsychopharmacology</i>. Elsevier, 2019. <a href=\"https://doi.org/10.1016/j.euroneuro.2019.09.039\">https://doi.org/10.1016/j.euroneuro.2019.09.039</a>.","ieee":"L. Knaus, D.-C. Tarlungeanu, and G. Novarino, “S.16.03 A homozygous missense mutation in SLC7A5 leads to autism spectrum disorder and microcephaly,” <i>European Neuropsychopharmacology</i>, vol. 29, no. Supplement 6. Elsevier, p. S11, 2019.","short":"L. Knaus, D.-C. Tarlungeanu, G. Novarino, European Neuropsychopharmacology 29 (2019) S11.","ama":"Knaus L, Tarlungeanu D-C, Novarino G. S.16.03 A homozygous missense mutation in SLC7A5 leads to autism spectrum disorder and microcephaly. <i>European Neuropsychopharmacology</i>. 2019;29(Supplement 6):S11. doi:<a href=\"https://doi.org/10.1016/j.euroneuro.2019.09.039\">10.1016/j.euroneuro.2019.09.039</a>","apa":"Knaus, L., Tarlungeanu, D.-C., &#38; Novarino, G. (2019). S.16.03 A homozygous missense mutation in SLC7A5 leads to autism spectrum disorder and microcephaly. <i>European Neuropsychopharmacology</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.euroneuro.2019.09.039\">https://doi.org/10.1016/j.euroneuro.2019.09.039</a>","ista":"Knaus L, Tarlungeanu D-C, Novarino G. 2019. S.16.03 A homozygous missense mutation in SLC7A5 leads to autism spectrum disorder and microcephaly. European Neuropsychopharmacology. 29(Supplement 6), S11.","mla":"Knaus, Lisa, et al. “S.16.03 A Homozygous Missense Mutation in SLC7A5 Leads to Autism Spectrum Disorder and Microcephaly.” <i>European Neuropsychopharmacology</i>, vol. 29, no. Supplement 6, Elsevier, 2019, p. S11, doi:<a href=\"https://doi.org/10.1016/j.euroneuro.2019.09.039\">10.1016/j.euroneuro.2019.09.039</a>."},"language":[{"iso":"eng"}],"issue":"Supplement 6","isi":1,"intvolume":"        29","status":"public","external_id":{"isi":["000502657500020"]},"date_created":"2020-01-30T10:06:15Z","volume":29,"title":"S.16.03 A homozygous missense mutation in SLC7A5 leads to autism spectrum disorder and microcephaly","date_updated":"2023-09-07T14:55:23Z","day":"13","oa_version":"None","type":"journal_article","month":"12","page":"S11","author":[{"last_name":"Knaus","first_name":"Lisa","id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87","full_name":"Knaus, Lisa"},{"full_name":"Tarlungeanu, Dora-Clara","id":"2ABCE612-F248-11E8-B48F-1D18A9856A87","last_name":"Tarlungeanu","first_name":"Dora-Clara"},{"orcid":"0000-0002-7673-7178","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","full_name":"Novarino, Gaia","last_name":"Novarino","first_name":"Gaia"}],"article_processing_charge":"No","article_type":"original","publication":"European Neuropsychopharmacology","_id":"7414","department":[{"_id":"GaNo"}],"year":"2019","publisher":"Elsevier","user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1"}]