The HSA21 gene EURL/C21ORF91 controls neurogenesis within the cerebral cortex and is implicated in the pathogenesis of Down Syndrome.

Shan Shan Li,Linh Ngo,Joanne Maria Britto,Hyo Jung Kang,Seong-Seng Tan,Hannah Kate Vanyai,Julian Ik-Tsen Heng,Hayley Daniella Cullen,Matilda Haas,Zhengdong Qu,You Jeong Heo,Tailoi Chan-Ling,Jenny Margaret Gunnersen

doi:10.1038/srep29514

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.

Highlights

It is recognised that HSA21-related aneuploidy disorders are a consequence of an improper dosage of triplicated genes, a concept which can be referred to as the “gene dosage hypothesis”[4,5]
Genetic association studies of HSA21-related aneuploidy disorders point to additional candidate genes beyond the DSCR which are important for neuronal development, and whose functions are likely to be relevant to the neurobiology of intellectual disability[18,19,20]
We report that EURL is expressed within the developing central nervous system (CNS) of mice and humans, and is detected in neural progenitor cells and postmitotic neurons of the embryonic cerebral cortex

Summary

Introduction

It is recognised that HSA21-related aneuploidy disorders are a consequence of an improper dosage of triplicated genes, a concept which can be referred to as the “gene dosage hypothesis”[4,5]. Genetic association studies of HSA21-related aneuploidy disorders point to additional candidate genes beyond the DSCR which are important for neuronal development, and whose functions are likely to be relevant to the neurobiology of intellectual disability[18,19,20]. Slavotinek and colleagues described a male infant with microcephaly which harboured a partial tetrasomy 21 ( comprising EURL) which did not encompass the Down Syndrome Critical Region[20]. Taken together, these observations suggest that perturbations to EURL may be a contributing genetic factor in the neurobiology of brain growth and intellectual disability. We highlight the concentration-dependent effects of EURL on neuronal development within the immature cerebral cortex, and suggest EURL as a contributory gene to the neurodevelopmental disorders arising from HSA21 aneuploidies in infants

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Conclusion