{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:26:27Z","timestamp":1792787187351,"version":"4.5.0"},"reference-count":55,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"39","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32030042"],"award-info":[{"award-number":["32030042"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 92357301"],"award-info":[{"award-number":["No. 92357301"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 32370726"],"award-info":[{"award-number":["No. 32370726"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Key Research and Development Program of China","award":["2024YFC2707002"],"award-info":[{"award-number":["2024YFC2707002"]}]},{"name":"National Key Research and Development Program of China","award":["2022YFA1104200"],"award-info":[{"award-number":["2022YFA1104200"]}]},{"name":"Shanghai Municipal Science and Technology Committee","award":["19411965000"],"award-info":[{"award-number":["19411965000"]}]},{"name":"the National Key Research and Development Program of China","award":["2021YFA1101302"],"award-info":[{"award-number":["2021YFA1101302"]}]},{"name":"Open Research Fund of State Key Laboratory of Genetic Engineering Fudan University","award":["SKLGE-2309"],"award-info":[{"award-number":["SKLGE-2309"]}],"id":[{"id":"https:\/\/ror.org\/01n3rg866","id-type":"ROR","asserted-by":"crossref"}]},{"name":"the STI2030-Major Projects","award":["no. 2021ZD0202801"],"award-info":[{"award-number":["no. 2021ZD0202801"]}]},{"name":"WY and SW Shanghai Children Hospital Fund","award":["2021YGZQ07"],"award-info":[{"award-number":["2021YGZQ07"]}]},{"name":"Shanghai Children Hospital Fund","award":["2022YGZM01"],"award-info":[{"award-number":["2022YGZM01"]}],"id":[{"id":"https:\/\/ror.org\/05pea1m70","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Open Research Fund of State Key 1027 Laboratory of Genetic Engineering, Fudan University","award":["SKLGE-2309"],"award-info":[{"award-number":["SKLGE-2309"]}]},{"name":"Three-Year Initiative Plan for Strengthening Public Health 1030 System Construction in Shanghai","award":["GWVI-3"],"award-info":[{"award-number":["GWVI-3"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,9,25]]},"abstract":"<jats:p>\n                    The MAPK-ERK1\/2 pathway plays a crucial role in neurodevelopment during embryogenesis, and the hyperactivation of this signaling cascade serves as a pathological hallmark for various neurodevelopmental disorders. Germline variants in\n                    <jats:italic toggle=\"yes\">TRAF7<\/jats:italic>\n                    , encoding a RING-type E3 ubiquitin ligase, are genetically associated with cardiac, facial, and digital anomalies with developmental delay (CAFDADD) syndrome; however, the downstream substrates of TRAF7 and the precise mechanism driving neurodevelopmental defects remain enigmatic. Here, we established a\n                    <jats:italic toggle=\"yes\">Traf7<\/jats:italic>\n                    <jats:sup>R654Q\/+<\/jats:sup>\n                    knock-in mouse model and patient-specific induced pluripotent stem cell (iPSC)\u2013derived human cortical organoids (hCOs) carrying the recurrent\n                    <jats:italic toggle=\"yes\">TRAF7<\/jats:italic>\n                    <jats:sup>R655Q<\/jats:sup>\n                    mutation. Heterozygous\n                    <jats:italic toggle=\"yes\">Traf7<\/jats:italic>\n                    <jats:sup>R654Q\/+<\/jats:sup>\n                    mice exhibited remarkable growth retardation, skeletal abnormalities, and neurobehavioral deficits, whereas mutant hCOs displayed early cortical neurogenesis defects, characterized by premature neural differentiation and a depleted progenitor pool. Mechanistically, biochemical analyses revealed that TRAF7 interacts with KRAS and NRAS to promote their polyubiquitination and subsequent proteasomal degradation, maintaining physiological homeostatic control over the downstream MAPK cascade. CAFDADD-associated TRAF7 variants exert a dominant-negative effect, disrupting WT protein function and causing the posttranslational accumulation of KRAS and NRAS, which fundamentally drives constitutive MAPK-ERK1\/2 pathway hyperactivation. Notably, pharmacological inhibition of MEK1\/2 with selumetinib suppressed ERK1\/2 hyperactivation, partially mitigated aberrant neuroepithelial morphology and neural differentiation in\n                    <jats:italic toggle=\"yes\">TRAF7<\/jats:italic>\n                    <jats:sup>R655Q\/+<\/jats:sup>\n                    hCOs, and improved brain-to-body weight ratios in\n                    <jats:italic toggle=\"yes\">Traf7<\/jats:italic>\n                    <jats:sup>R654Q\/+<\/jats:sup>\n                    mice. Together, our findings identify TRAF7 as a critical posttranslational regulator of RAS proteostasis during development and uncover a pivotal mechanistic link between impaired RAS ubiquitination and CAFDADD pathogenesis, providing preliminary clinical-front evidence for targeting the MAPK pathway to manage ongoing developmental deficits in TRAF7-associated disorders.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adw8672","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:58:53Z","timestamp":1790359133000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["<i>TRAF7<\/i>\n                    mutations stabilize K\/NRAS and hyperactivate MAPK signaling to cause CAFDADD neurodevelopmental defects"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9025-3228","authenticated-orcid":true,"given":"Man","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China."},{"name":"Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China."},{"name":"College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2379-6323","authenticated-orcid":true,"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Histology and Embryology, School of Basic Medical Science, Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozhen","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China."},{"name":"Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China."},{"name":"College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4920-1546","authenticated-orcid":true,"given":"Jingxuan","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojun","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China."},{"name":"Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China."},{"name":"College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maosen","family":"Dou","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9898-4607","authenticated-orcid":true,"given":"Wei","family":"Yu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China."},{"name":"Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China."},{"name":"College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhao","family":"Weng","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China."},{"name":"Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China."},{"name":"College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0963-6286","authenticated-orcid":true,"given":"Dingding","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China."},{"name":"Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China."},{"name":"College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Lan","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China."},{"name":"Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China."},{"name":"College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Zhao","sequence":"additional","affiliation":[{"name":"Shanghai Engineering Research Center for Big Data in Pediatric Precision Medicine, Center for Biomedical Informatics, School of Medicine, Shanghai Jiao Tong University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5752-6439","authenticated-orcid":true,"given":"Chenji","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanghai Pudong Hospital, Fudan University Pudong Medical Center, State Key Laboratory of Genetics and Development of Complex Phenotypes, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9399-155X","authenticated-orcid":true,"given":"Lixiang","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Histology and Embryology, School of Basic Medical Science, Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2147-3352","authenticated-orcid":true,"given":"Nan-Jie","family":"Xu","sequence":"additional","affiliation":[{"name":"Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2245-2273","authenticated-orcid":true,"given":"Shengnan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Shanghai Children\u2019s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China."},{"name":"Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China."},{"name":"College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China."},{"name":"NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology and Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.06.005"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-020-0792-7"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2024.03.008"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2317601121"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.24011"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1086"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.107474"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/jmcb\/mjad083"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2214997120"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a011254"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8503013"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20748"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.32015"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi400679q"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20955"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2021.10.009"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-01081-0"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.scr.2021.102377"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5488-08.2009"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0679-08.2008"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-3669"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2017.179"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2899-04.2005"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.23879"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2010.04.004"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.21037\/atm-21-597"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.070276"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2005.01.013"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.32151"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-1150"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminoncol.2015.09.023"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2024.129561"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-021-02646-w"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003851"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01710-0"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2017-00232"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.07.011"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2443.2003.00680.x"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2109"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.11.19.2468"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1418126111"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(04)00085-6"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-04-281527"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.633661"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.007112"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11164735"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.4719"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.215426"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-021-00749-w"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-023-01675-9"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-019-0606-y"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1063(2000)10:1<47::AID-HIPO5>3.0.CO;2-6"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2254"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3001868"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-63585-x"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.adw8672","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:02:12Z","timestamp":1790359332000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.adw8672"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,25]]},"references-count":55,"journal-issue":{"issue":"39","published-print":{"date-parts":[[2026,9,25]]}},"alternative-id":["10.1126\/sciadv.adw8672"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.adw8672","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,25]]},"assertion":[{"value":"2025-03-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadw8672"}}