RT Journal Article
SR Electronic
T1 Cerebral organoid proteomics reveals signatures of dysregulated cortical development associated with human trisomy 21
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 315317
DO 10.1101/315317
A1 Tristan D. McClure-Begley
A1 Christopher C. Ebmeier
A1 Kerri E. Ball
A1 Jeremy R. Jacobsen
A1 Igor Kogut
A1 Ganna Bilousova
A1 Michael W. Klymkowsky
A1 William M. Old
YR 2018
UL http://biorxiv.org/content/early/2018/05/05/315317.1.abstract
AB Human trisomy 21 (Down syndrome) is the most common genetic cause of intellectual disability, and is associated with complex perturbations in protein expression during development. Brain region-specific alterations in neuronal density and composition originate prenatally in trisomy 21 individuals, and are presumed to underlie the intellectual disability and early onset neurodegeneration that characterizes Down syndrome. However, the mechanisms by which chromosome 21 aneuploidy drives alterations in the central nervous system are not well understood, particularly in brain regions that are uniquely human and thus inaccessible to established animal models. Cerebral organoids are pluripotent stem cell derived models of prenatal brain development that have been used to deepen our understanding of the atypical processes associated with human neurobiological disorders, and thus provide a promising avenue to explore the molecular basis for neurodevelopmental alterations in trisomy 21. Here, we employ high-resolution label-free mass spectrometry to map proteomic changes over the course of trisomy 21 cerebral organoid development, and evaluate the proteomic alterations in response to treatment with harmine, a small molecule inhibitor of the chromosome 21 encoded protein kinase DYRK1A. Our results reveal trisomy 21 specific dysregulation of networks associated with neurogenesis, axon guidance and extracellular matrix remodeling. We find significant overlap of these networks show significant overlap with previously identified dysregulated gene expression modules identified in trisomy 21 fetal brain tissue. We show that harmine leads to partial normalization of key regulators of cortical development, including WNT7A and the transcription factors TBR1, BCL11A, and POU3F2, pointing to a causative role for DYRK1A over-expression in neurodevelopmental effects of human trisomy 21.ABBREVIATIONSHSA21human chromosome 21DSDown syndromeCOcerebral organoidEBembryoid bodyiPSCinduced pluripotent stem cellDMSOdimethyl sulfoxideEdU5-ethynyl-2’-deoxyuridineFDRfalse discovery rateT21the trisomy 21 C2-4 iPSC lineD21the euploid I50-2 iPSC lineTX100Triton X-100; NS, neurosphereDPBSDulbecco’s phosphate-buffered salinePBSphosphate-buffered salineAGCAutomatic Gain ControlLFQlabel-free quantitationPCAprincipal component analysisECMextracellular matrixWGCNAweighted gene co-expression network analysis