title: The HSA21 gene EURL/C21ORF91 controls neurogenesis within the cerebral cortex and is implicated in the pathogenesis of Down Syndrome.
abstract: Copy number variations to chromosome 21 (HSA21) cause intellectual disability and Down Syndrome, but our understanding of the HSA21 genetic factors which contribute to fetal brain development remains incomplete. Here, we focussed on the neurodevelopmental functions for EURL (also known as C21ORF91, Refseq Gene ID:54149), a protein-coding gene at the centromeric boundary of the Down Syndrome Critical Region (DSCR) of HSA21. We report that EURL is expressed during human and mouse cerebral cortex development, and we report that alterations to EURL mRNA levels within the human brain underlie Down Syndrome. Our gene perturbation studies in mice demonstrate that disruptions to Eurl impair progenitor proliferation and neuronal differentiation. Also, we find that disruptions to Eurl impair the long-term positioning and dendritic spine densities of cortical projection neurons. We provide evidence that EURL interacts with the coiled-coil domain-containing protein CCDC85B so as to modulate β-catenin levels in cells. Further, we utilised a fluorescent reporter (8xTOPFLASHd2EGFP) to demonstrate that disruptions to Eurl alter β-catenin signalling in vitro as well as in vivo. Together, these studies highlight EURL as an important new player in neuronal development that is likely to impact on the neuropathogenesis of HSA21-related disorders including Down Syndrome.
authors.affiliation: EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Shan Shan
authors.initials: SS
authors.lastname: Li
authors.affiliation: EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Qu
authors.affiliation: EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Matilda
authors.initials: M
authors.lastname: Haas
authors.affiliation: EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia.|The Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Crawley, Western Australia, 6009, Australia.
authors.forename: Linh
authors.initials: L
authors.lastname: Ngo
authors.affiliation: Department of Life Science, Chung-Ang University, Seoul, Korea.
authors.forename: You Jeong
authors.initials: YJ
authors.lastname: Heo
authors.affiliation: Department of Life Science, Chung-Ang University, Seoul, Korea.|Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Hyo Jung
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia.
authors.forename: Joanne Maria
authors.initials: JM
authors.lastname: Britto
authors.affiliation: The Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Crawley, Western Australia, 6009, Australia.
authors.forename: Hayley Daniella
authors.initials: HD
authors.lastname: Cullen
authors.affiliation: The Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Crawley, Western Australia, 6009, Australia.
authors.forename: Hannah Kate
authors.initials: HK
authors.lastname: Vanyai
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia.
authors.forename: Seong-Seng
authors.initials: SS
authors.lastname: Tan
authors.affiliation: Discipline of Anatomy, School of Medical Sciences, Bosch Institute, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Tailoi
authors.initials: T
authors.lastname: Chan-Ling
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia.|The Anatomy and Neuroscience Department, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Jenny Margaret
authors.initials: JM
authors.lastname: Gunnersen
authors.affiliation: EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia.|The Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Crawley, Western Australia, 6009, Australia.
authors.forename: Julian Ik-Tsen
authors.initials: JI
authors.lastname: Heng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000196:embryology*; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D049229:Dendritic Spines / Q000473:pathology; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000627571:C21orf91 protein, human; C101409:CCDC85B protein, human; C495270:CTNNB1 protein, human; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D051176:beta Catenin