{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:23:31Z","timestamp":1790778211854,"version":"4.1.0"},"reference-count":100,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T00:00:00Z","timestamp":1711584000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001664","name":"medical faculty of Heinrich Heine University D\u00fcsseldorf, the Leibniz Association","doi-asserted-by":"publisher","award":["K246\/2019"],"award-info":[{"award-number":["K246\/2019"]}],"id":[{"id":"10.13039\/501100001664","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001664","name":"medical faculty of Heinrich Heine University D\u00fcsseldorf, the Leibniz Association","doi-asserted-by":"publisher","award":["417677437\/GRK2578"],"award-info":[{"award-number":["417677437\/GRK2578"]}],"id":[{"id":"10.13039\/501100001664","id-type":"DOI","asserted-by":"publisher"}]},{"name":"German Research Foundation","award":["K246\/2019"],"award-info":[{"award-number":["K246\/2019"]}]},{"name":"German Research Foundation","award":["417677437\/GRK2578"],"award-info":[{"award-number":["417677437\/GRK2578"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cockayne syndrome (CS) is a rare hereditary autosomal recessive disorder primarily caused by mutations in Cockayne syndrome protein A (CSA) or B (CSB). While many of the functions of CSB have been at least partially elucidated, little is known about the actual developmental dysregulation in this devasting disorder. Of particular interest is the regulation of cerebral development as the most debilitating symptoms are of neurological nature. We generated neurospheres and cerebral organoids utilizing Cockayne syndrome B protein (CSB)-deficient induced pluripotent stem cells derived from two patients with distinct severity levels of CS and healthy controls. The transcriptome of both developmental timepoints was explored using RNA-Seq and bioinformatic analysis to identify dysregulated biological processes common to both patients with CS in comparison to the control. CSB-deficient neurospheres displayed upregulation of the VEGFA-VEGFR2 signalling pathway, vesicle-mediated transport and head development. CSB-deficient cerebral organoids exhibited downregulation of brain development, neuron projection development and synaptic signalling. We further identified the upregulation of steroid biosynthesis as common to both timepoints, in particular the upregulation of the cholesterol biosynthesis branch. Our results provide insights into the neurodevelopmental dysregulation in patients with CS and strengthen the theory that CS is not only a neurodegenerative but also a neurodevelopmental disorder.<\/jats:p>","DOI":"10.3390\/cells13070591","type":"journal-article","created":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T12:52:12Z","timestamp":1711630332000},"page":"591","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Cockayne Syndrome Patient iPSC-Derived Brain Organoids and Neurospheres Show Early Transcriptional Dysregulation of Biological Processes Associated with Brain Development and Metabolism"],"prefix":"10.3390","volume":"13","author":[{"given":"Leon-Phillip","family":"Szepanowski","sequence":"first","affiliation":[{"name":"Institute for Stem Cell Research and Regenerative Medicine, University Hospital D\u00fcsseldorf, Moorenstrasse 5, D-40225 Duesseldorf, Germany"},{"name":"IUF\u2014Leibniz Research Institute for Environmental Medicine, Auf\u2019m Hennekamp 50, D-40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9153-7051","authenticated-orcid":false,"given":"Wasco","family":"Wruck","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell Research and Regenerative Medicine, University Hospital D\u00fcsseldorf, Moorenstrasse 5, D-40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Kapr","sequence":"additional","affiliation":[{"name":"IUF\u2014Leibniz Research Institute for Environmental Medicine, Auf\u2019m Hennekamp 50, D-40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5863-6448","authenticated-orcid":false,"given":"Andrea","family":"Rossi","sequence":"additional","affiliation":[{"name":"IUF\u2014Leibniz Research Institute for Environmental Medicine, Auf\u2019m Hennekamp 50, D-40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7454-679X","authenticated-orcid":false,"given":"Ellen","family":"Fritsche","sequence":"additional","affiliation":[{"name":"IUF\u2014Leibniz Research Institute for Environmental Medicine, Auf\u2019m Hennekamp 50, D-40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8433-1517","authenticated-orcid":false,"given":"Jean","family":"Krutmann","sequence":"additional","affiliation":[{"name":"IUF\u2014Leibniz Research Institute for Environmental Medicine, Auf\u2019m Hennekamp 50, D-40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6075-6761","authenticated-orcid":false,"given":"James","family":"Adjaye","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell Research and Regenerative Medicine, University Hospital D\u00fcsseldorf, Moorenstrasse 5, D-40225 Duesseldorf, Germany"},{"name":"Zayed Centre for Research into Rare Diseases in Children (ZCR), University College London (UCL)\u2014EGA Institute for Women\u2019s Health, 20 Guilford Street, London WC1N 1DZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1136\/adc.11.61.1","article-title":"Dwarfism with retinal atrophy and deafness","volume":"11","author":"Cockayne","year":"1936","journal-title":"Arch. Dis. Child."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1086\/380399","article-title":"Cockayne syndrome group B cellular and biochemical functions","volume":"73","author":"Licht","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1002\/ajmg.1320420115","article-title":"Cockayne syndrome: Review of 140 cases","volume":"42","author":"Nance","year":"1992","journal-title":"Am. J. Med. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.mad.2013.02.006","article-title":"Cockayne syndrome: The expanding clinical and mutational spectrum","volume":"134","author":"Laugel","year":"2013","journal-title":"Mech. Ageing Dev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.mad.2009.07.006","article-title":"Neuropathology of Cockayne syndrome: Evidence for impaired development, premature aging, and neurodegeneration","volume":"130","author":"Weidenheim","year":"2009","journal-title":"Mech. Ageing Dev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/nrm3822","article-title":"Understanding nucleotide excision repair and its roles in cancer and ageing","volume":"15","author":"Marteijn","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Gupta, S., You, P., SenGupta, T., Nilsen, H., and Sharma, K. (2021). Crosstalk between different DNA repair pathways contributes to neurodegenerative diseases. Biology, 10.","DOI":"10.3390\/biology10020163"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9270","DOI":"10.1074\/jbc.M807006200","article-title":"Cockayne syndrome group B protein stimulates repair of formamidopyrimidines by NEIL1 DNA glycosylase","volume":"284","author":"Muftuoglu","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7625","DOI":"10.1128\/MCB.25.17.7625-7636.2005","article-title":"Cooperation of the Cockayne syndrome group B protein and poly (ADP-ribose) polymerase 1 in the response to oxidative stress","volume":"25","author":"Thorslund","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4103","DOI":"10.1093\/nar\/gkm404","article-title":"Cockayne syndrome B protein stimulates apurinic endonuclease 1 activity and protects against agents that introduce base excision repair intermediates","volume":"35","author":"Wong","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2418","DOI":"10.1093\/nar\/gkab085","article-title":"Current and emerging roles of Cockayne syndrome group B (CSB) protein","volume":"49","author":"Tiwari","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.15252\/embj.201490041","article-title":"Cockayne syndrome group B protein regulates DNA double-strand break repair and checkpoint activation","volume":"34","author":"Batenburg","year":"2015","journal-title":"EMBO J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1093\/nar\/gku1279","article-title":"CSB interacts with SNM1A and promotes DNA interstrand crosslink processing","volume":"43","author":"Iyama","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.jmb.2015.11.020","article-title":"Elements That Regulate the DNA Damage Response of Proteins Defective in Cockayne Syndrome","volume":"428","author":"Iyama","year":"2016","journal-title":"J. Mol. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4306","DOI":"10.1073\/pnas.94.9.4306","article-title":"Reduced RNA polymerase II transcription in intact and permeabilized Cockayne syndrome group B cells","volume":"94","author":"Balajee","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"14454","DOI":"10.1073\/pnas.1412569111","article-title":"Dysregulation of gene expression as a cause of Cockayne syndrome neurological disease","volume":"111","author":"Wang","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/S0092-8674(00)80223-8","article-title":"Defective transcription-coupled repair in Cockayne syndrome B mice is associated with skin cancer predisposition","volume":"89","author":"Berg","year":"1997","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S1568-7864(01)00010-6","article-title":"UVB radiation-induced cancer predisposition in Cockayne syndrome group A (Csa) mutant mice","volume":"1","author":"Meira","year":"2002","journal-title":"DNA Repair"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.mad.2013.04.003","article-title":"Cockayne syndrome pathogenesis: Lessons from mouse models","volume":"134","author":"Jaarsma","year":"2013","journal-title":"Mech. Ageing Dev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1128\/MCB.01229-08","article-title":"An Xpb mouse model for combined xeroderma pigmentosum and cockayne syndrome reveals progeroid features upon further attenuation of DNA repair","volume":"29","author":"Andressoo","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.ccr.2006.05.027","article-title":"An Xpd mouse model for the combined xeroderma pigmentosum\/Cockayne syndrome exhibiting both cancer predisposition and segmental progeria","volume":"10","author":"Andressoo","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1128\/MCB.19.3.2366","article-title":"Postnatal growth failure, short life span, and early onset of cellular senescence and subsequent immortalization in mice lacking the xeroderma pigmentosum group G gene","volume":"19","author":"Harada","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.arr.2016.08.002","article-title":"Cockayne syndrome: Clinical features, model systems and pathways","volume":"33","author":"Karikkineth","year":"2017","journal-title":"Ageing Res. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3825","DOI":"10.1093\/hmg\/dds211","article-title":"Evidence for premature aging due to oxidative stress in iPSCs from Cockayne syndrome","volume":"21","author":"Andrade","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"E2261","DOI":"10.1073\/pnas.1220071110","article-title":"Regulatory interplay of Cockayne syndrome B ATPase and stress-response gene ATF3 following genotoxic stress","volume":"110","author":"Kristensen","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2554","DOI":"10.1016\/j.celrep.2016.02.051","article-title":"Pharmacological bypass of Cockayne syndrome B function in neuronal differentiation","volume":"14","author":"Wang","year":"2016","journal-title":"Cell Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1093\/hmg\/ddw008","article-title":"Cockayne syndrome-derived neurons display reduced synapse density and altered neural network synchrony","volume":"25","author":"Vessoni","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s13238-019-0623-2","article-title":"Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR\/Cas9-mediated gene correction","volume":"11","author":"Wang","year":"2020","journal-title":"Protein Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2100131","DOI":"10.1002\/adhm.202100131","article-title":"Human Induced Pluripotent Stem Cell-Derived Neural Progenitor Cells Produce Distinct Neural 3D In Vitro Models Depending on Alginate\/Gellan Gum\/Laminin Hydrogel Blend Properties","volume":"10","author":"Kapr","year":"2021","journal-title":"Adv. Healthc. Mater."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"102456","DOI":"10.1016\/j.scr.2021.102456","article-title":"Generation of an induced pluripotent stem cell line (IUFi001) from a Cockayne syndrome patient carrying a mutation in the ERCC6 gene","volume":"55","author":"Martins","year":"2021","journal-title":"Stem Cell Res."},{"key":"ref_31","unstructured":"Hofrichter, M. (2016). Establishment of a hiPSC-Based In Vitro Model to Study Environmental and Genetic Disturbances of Neurodevelopmental Processes. [Inaugural-Dissertation, Heinrich-Heine-Universit\u00e4t D\u00fcsseldorf]."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s12015-010-9209-3","article-title":"A cyclic AMP analog, 8-Br-cAMP, enhances the induction of pluripotency in human fibroblast cells","volume":"7","author":"Wang","year":"2011","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Martins, S., Erichsen, L., Datsi, A., Wruck, W., Goering, W., Chatzantonaki, E., de Amorim, V.C.M., Rossi, A., Chrzanowska, K.H., and Adjaye, J. (2022). Impaired p53-mediated DNA damage response contributes to microcephaly in Nijmegen Breakage Syndrome patient-derived cerebral organoids. Cells, 11.","DOI":"10.3390\/cells11050802"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Martins, S., M\u00fcller-Schiffmann, A., Erichsen, L., Bohndorf, M., Wruck, W., Sleegers, K., Van Broeckhoven, C., Korth, C., and Adjaye, J. (2020). IPSC-derived neuronal cultures carrying the Alzheimer\u2019s disease associated TREM2 R47H variant enables the construction of an A\u03b2-induced gene regulatory network. Int. J. Mol. Sci., 21.","DOI":"10.1101\/652446"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1038\/s41596-018-0032-7","article-title":"Generation and assembly of human brain region-specific three-dimensional cultures","volume":"13","author":"Sloan","year":"2018","journal-title":"Nat. Protoc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1038\/nprot.2013.106","article-title":"Directed differentiation of forebrain GABA interneurons from human pluripotent stem cells","volume":"8","author":"Liu","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: A fast spliced aligner with low memory requirements","volume":"12","author":"Kim","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Gentleman, R.C., Carey, V.J., Bates, D.M., Bolstad, B., Dettling, M., Dudoit, S., Ellis, B., Gautier, L., Ge, Y., and Gentry, J. (2004). Bioconductor: Open software development for computational biology and bioinformatics. Genome Biol., 5.","DOI":"10.1186\/gb-2004-5-10-r80"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Chen, H., and Boutros, P.C. (2011). VennDiagram: A package for the generation of highly-customizable Venn and Euler diagrams in R. BMC Bioinform., 12.","DOI":"10.1186\/1471-2105-12-35"},{"key":"ref_40","unstructured":"Warnes, M.G.R., Bolker, B., Bonebakker, L., Gentleman, R., Huber, W., and Liaw, A. (2016). Various R Programming Tools for Plotting Data, R Foundation for Statistical Computing."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1093\/bioinformatics\/btl567","article-title":"Using GOstats to test gene lists for GO term association","volume":"23","author":"Falcon","year":"2007","journal-title":"Bioinformatics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"D353","DOI":"10.1093\/nar\/gkw1092","article-title":"KEGG: New perspectives on genomes, pathways, diseases and drugs","volume":"45","author":"Kanehisa","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1002\/pro.3715","article-title":"Toward understanding the origin and evolution of cellular organisms","volume":"28","author":"Kanehisa","year":"2019","journal-title":"Protein Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"D587","DOI":"10.1093\/nar\/gkac963","article-title":"KEGG for taxonomy-based analysis of pathways and genomes","volume":"51","author":"Kanehisa","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Wickham, H. (2009). ggplot2: Elegant Grophics for Data Analysis, Springer.","DOI":"10.1007\/978-0-387-98141-3"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1038\/nrn2722","article-title":"The Allen brain atlas: 5 years and beyond","volume":"10","author":"Jones","year":"2009","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"H\u00e4nzelmann, S., Castelo, R., and Guinney, J. (2013). GSVA: Gene set variation analysis for microarray and RNA-seq data. BMC Bioinform., 14.","DOI":"10.1186\/1471-2105-14-7"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/nature13185","article-title":"Transcriptional landscape of the prenatal human brain","volume":"508","author":"Miller","year":"2014","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/nature12517","article-title":"Cerebral organoids model human brain development and microcephaly","volume":"501","author":"Lancaster","year":"2013","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Qiang, M., Khalid, F., Phan, T., Ludwig, C., Scharffetter-Kochanek, K., and Iben, S. (2021). Cockayne syndrome-associated CSA and CSB mutations impair ribosome biogenesis, ribosomal protein stability, and global protein folding. Cells, 10.","DOI":"10.3390\/cells10071616"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1016\/j.celrep.2018.04.041","article-title":"Loss of proteostasis is a pathomechanism in Cockayne syndrome","volume":"23","author":"Alupei","year":"2018","journal-title":"Cell Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e662","DOI":"10.1038\/tp.2015.118","article-title":"Increased abundance of translation machinery in stem cell\u2013derived neural progenitor cells from four schizophrenia patients","volume":"5","author":"Topol","year":"2015","journal-title":"Transl. Psychiatry"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"11946","DOI":"10.1073\/pnas.182296499","article-title":"Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo","volume":"99","author":"Jin","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1242\/dev.072348","article-title":"Diverse roles for VEGF-A in the nervous system","volume":"139","author":"Mackenzie","year":"2012","journal-title":"Development"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/j.1750-3639.2004.tb00060.x","article-title":"Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor","volume":"14","author":"Wachs","year":"2004","journal-title":"Brain Pathol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"11036","DOI":"10.1523\/JNEUROSCI.23-35-11036.2003","article-title":"Neurotrophic effects of vascular endothelial growth factor on organotypic cortical explants and primary cortical neurons","volume":"23","author":"Rosenstein","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"10242","DOI":"10.1073\/pnas.97.18.10242","article-title":"Vascular endothelial growth factor: Direct neuroprotective effect in in vitro ischemia","volume":"97","author":"Jin","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1016\/j.neuint.2011.07.005","article-title":"PI3-K\/Akt and ERK pathways activated by VEGF play opposite roles in MPP+-induced neuronal apoptosis","volume":"59","author":"Cui","year":"2011","journal-title":"Neurochem. Int."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1096\/fj.00-0495fje","article-title":"Vascular endothelial growth factor rescues hippocampal neurons from glutamate-induced toxicity: Signal transduction cascades","volume":"15","author":"Matsuzaki","year":"2001","journal-title":"FASEB J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.dnarep.2012.11.004","article-title":"Cockayne syndrome b maintains neural precursor function","volume":"12","author":"Sacco","year":"2013","journal-title":"DNA Repair"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1136\/jmg.2007.050294","article-title":"Cargos and genes: Insights into vesicular transport from inherited human disease","volume":"44","author":"Gissen","year":"2007","journal-title":"J. Med. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"dmm043448","DOI":"10.1242\/dmm.043448","article-title":"Membrane trafficking in health and disease","volume":"13","author":"Yarwood","year":"2020","journal-title":"Dis. Models Mech."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1007\/s13238-017-0479-2","article-title":"Recapitulating cortical development with organoid culture in vitro and modeling abnormal spindle-like (ASPM related primary) microcephaly disease","volume":"8","author":"Li","year":"2017","journal-title":"Protein Cell"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"803","DOI":"10.15252\/embj.201593679","article-title":"CPAP promotes timely cilium disassembly to maintain neural progenitor pool","volume":"35","author":"Gabriel","year":"2016","journal-title":"EMBO J."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1038\/cr.2015.85","article-title":"DNA damage and repair regulate neuronal gene expression","volume":"25","author":"Su","year":"2015","journal-title":"Cell Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1002\/jcp.24315","article-title":"Analysis of the protein network of cholesterol homeostasis in different brain regions: An age and sex dependent perspective","volume":"228","author":"Segatto","year":"2013","journal-title":"J. Cell. Physiol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s12944-019-0965-z","article-title":"Role of cholesterol and sphingolipids in brain development and neurological diseases","volume":"18","author":"Hussain","year":"2019","journal-title":"Lipids Health Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1002\/celc.201600738","article-title":"Determining the composition of active Cholesterol in the plasma membrane of single cells by using Electrochemiluminescence","volume":"4","author":"Zuo","year":"2017","journal-title":"ChemElectroChem"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.mcn.2005.02.006","article-title":"Multiple mechanisms mediate cholesterol-induced synaptogenesis in a CNS neuron","volume":"29","author":"Goritz","year":"2005","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_72","unstructured":"Adibhatla, R.M., and Hatcher, J. (2008). Lipids in Health and Disease, Springer."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.15252\/embr.201439225","article-title":"Cholesterol in brain disease: Sometimes determinant and frequently implicated","volume":"15","author":"Pfrieger","year":"2014","journal-title":"EMBO Rep."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1126\/science.294.5545.1354","article-title":"CNS synaptogenesis promoted by glia-derived cholesterol","volume":"294","author":"Mauch","year":"2001","journal-title":"Science"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1093\/brain\/awv166","article-title":"CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer\u2019s disease","volume":"138","author":"Djelti","year":"2015","journal-title":"Brain"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2808","DOI":"10.1093\/hmg\/ddv042","article-title":"Analysis of hedgehog signaling in cerebellar granule cell precursors in a conditional Nsdhl allele demonstrates an essential role for cholesterol in postnatal CNS development","volume":"24","author":"Cunningham","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1016\/B978-0-444-59565-2.00054-X","article-title":"Cholesterol metabolism deficiency","volume":"Volume 113","author":"Jira","year":"2013","journal-title":"Handbook of Clinical Neurology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"8350","DOI":"10.1073\/pnas.0903541106","article-title":"Ablation of cholesterol biosynthesis in neural stem cells increases their VEGF expression and angiogenesis but causes neuron apoptosis","volume":"106","author":"Saito","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Xiong, Y., Zhang, Y., Xiong, S., and Williams-Villalobo, A.E. (2020). A glance of p53 functions in brain development, neural stem cells, and brain cancer. Biology, 9.","DOI":"10.3390\/biology9090285"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3226","DOI":"10.1073\/pnas.0508500103","article-title":"Synergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development","volume":"103","author":"Xiong","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3719","DOI":"10.4161\/cc.10.21.17905","article-title":"CSA and CSB proteins interact with p53 and regulate its Mdm2-dependent ubiquitination","volume":"10","author":"Latini","year":"2011","journal-title":"Cell Cycle"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Jaarsma, D., van der Pluijm, I., de Waard, M.C., Haasdijk, E.D., Brandt, R., Vermeij, M., Rijksen, Y., Maas, A., van Steeg, H., and Hoeijmakers, J.H. (2011). Age-related neuronal degeneration: Complementary roles of nucleotide excision repair and transcription-coupled repair in preventing neuropathology. PLoS Genet., 7.","DOI":"10.1371\/journal.pgen.1002405"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1038\/emboj.2008.180","article-title":"CSB protein is (a direct target of HIF-1 and) a critical mediator of the hypoxic response","volume":"27","author":"Filippi","year":"2008","journal-title":"EMBO J."},{"key":"ref_84","unstructured":"Proietti-De-Santis, L., Laugel, V., and Prantera, G. (2019). Chromatin Signaling and Neurological Disorders, Elsevier."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"693","DOI":"10.4161\/cc.8.5.7754","article-title":"Cockayne syndrome B protein (CSB): Linking p53, HIF-1 and p300 to robustness, lifespan, cancer and cell fate decisions","volume":"8","author":"Frontini","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1016\/j.neuroscience.2008.10.052","article-title":"p53 regulates the self-renewal and differentiation of neural precursors","volume":"158","author":"Bragado","year":"2009","journal-title":"Neuroscience"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1093\/carcin\/bgq101","article-title":"p53 is balancing development, differentiation and de-differentiation to assure cancer prevention","volume":"31","author":"Molchadsky","year":"2010","journal-title":"Carcinogenesis"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/0167-4781(88)90136-4","article-title":"The phosphoprotein p53 is down-regulated post-transcriptionally during embryogenesis in vertebrates","volume":"950","author":"Louis","year":"1988","journal-title":"Biochim. Biophys. Acta (BBA)-Gene Struct. Expr."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1242\/dev.113.3.857","article-title":"Expression of p53 during mouse embryogenesis","volume":"113","author":"Schmid","year":"1991","journal-title":"Development"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"e1268","DOI":"10.1038\/cddis.2014.228","article-title":"The cockayne syndrome B protein is essential for neuronal differentiation and neuritogenesis","volume":"5","author":"Ciaffardini","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.1093\/humrep\/den262","article-title":"Distinct GAGE and MAGE-A expression during early human development indicate specific roles in lineage differentiation","volume":"23","author":"Gjerstorff","year":"2008","journal-title":"Hum. Reprod."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"119257","DOI":"10.1016\/j.gep.2022.119257","article-title":"Differential expression of the Tmem132 family genes in the developing mouse nervous system","volume":"45","author":"Wang","year":"2022","journal-title":"Gene Expr. Patterns"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s11689-020-09317-2","article-title":"Transcriptome analysis of neural progenitor cells derived from Lowe syndrome induced pluripotent stem cells: Identification of candidate genes for the neurodevelopmental and eye manifestations","volume":"12","author":"Liu","year":"2020","journal-title":"J. Neurodev. Disord."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.stem.2021.09.008","article-title":"A cis-acting structural variation at the ZNF558 locus controls a gene regulatory network in human brain development","volume":"29","author":"Johansson","year":"2022","journal-title":"Cell Stem Cell"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1093\/jmcb\/mju005","article-title":"TRIM4 modulates type I interferon induction and cellular antiviral response by targeting RIG-I for K63-linked ubiquitination","volume":"6","author":"Yan","year":"2014","journal-title":"J. Mol. Cell Biol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2201701","DOI":"10.1002\/advs.202201701","article-title":"The E3 Ligase TRIM4 Facilitates SET Ubiquitin-Mediated Degradation to Enhance ER-\u03b1 Action in Breast Cancer","volume":"9","author":"Han","year":"2022","journal-title":"Adv. Sci."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2934","DOI":"10.1002\/jcp.30065","article-title":"TRIM4 interacts with TRPM8 and regulates its channel function through K423-mediated ubiquitination","volume":"236","author":"Huang","year":"2021","journal-title":"J. Cell. Physiol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s13148-018-0603-z","article-title":"TRIM4 is associated with neural tube defects based on genome-wide DNA methylation analysis","volume":"11","author":"Zhang","year":"2019","journal-title":"Clin. Epigenet."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"102696","DOI":"10.1016\/j.dnarep.2019.102696","article-title":"Multisystem analyses of two Cockayne syndrome associated proteins CSA and CSB reveal shared and unique functions","volume":"83","author":"Wu","year":"2019","journal-title":"DNA Repair"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.dnarep.2013.04.018","article-title":"Blinded by the UV light: How the focus on transcription-coupled NER has distracted from understanding the mechanisms of Cockayne syndrome neurologic disease","volume":"12","author":"Brooks","year":"2013","journal-title":"DNA Repair"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/7\/591\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:20:28Z","timestamp":1760106028000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/7\/591"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,28]]},"references-count":100,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["cells13070591"],"URL":"https:\/\/doi.org\/10.3390\/cells13070591","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.10.17.562706","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,28]]}}}