Inhibition of DYRK1A disrupts neural lineage specificationin human pluripotent stem cells

被引：23

作者：

Bellmaine, Stephanie F. ^{[1
,2
,3
]}

Ovchinnikov, Dmitry A. ^{[4
]}

Manallack, David T. ^{[5
]}

Cuddy, Claire E. ^{[2
]}

Elefanty, Andrew G. ^{[6
,7
,8
]}

Stanley, Edouard G. ^{[6
,7
,8
]}

Wolvetang, Ernst J. ^{[4
]}

Williams, Spencer J. ^{[1
,3
]}

Pera, Martin ^{[2
,9
]}

机构：

[1] Univ Melbourne, Sch Chem, Melbourne, Vic, Australia

[2] Univ Melbourne, Dept Anat & Neurosci, Melbourne, Vic, Australia

[3] Univ Melbourne, Mol Sci & Biotechnol Inst Bio21, Melbourne, Vic, Australia

[4] Univ Queensland, Australian Inst Bioengn & Nanotechnol, Brisbane, Qld, Australia

[5] Monash Univ, Fac Pharm & Pharmaceut Sci, Monash Inst Pharmaceut Sci, Melbourne, Vic, Australia

[6] Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic, Australia

[7] Univ Melbourne, Fac Med Dent & Hlth Sci, Dept Anat & Neurosci, Melbourne, Vic, Australia

[8] Monash Univ, Fac Med Nursing & Hlth Sci, Dept Anat & Dev Biol, Melbourne, Vic, Australia

[9] Florey Neurosci & Mental Hlth Inst, Walter & Eliza Hall Inst Med Res, Melbourne, Vic, Australia

来源：

ELIFE | 2017年 / 6卷

基金：

澳大利亚研究理事会; 英国医学研究理事会;

关键词：

SYNDROMIC INTELLECTUAL DISABILITY; PROTEIN-KINASE DYRK1A; DOWN-SYNDROME; NEURONAL DIFFERENTIATION; ALZHEIMERS-DISEASE; CYCLE EXIT; GENE; PROLIFERATION; FATE; MNB/DYRK1A;

D O I：

10.7554/eLife.24502

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Genetic analysis has revealed that the dual specificity protein kinase DYRK1A has multiple roles in the development of the central nervous system. Increased DYRK1A gene dosage, such as occurs in Down syndrome, is known to affect neural progenitor cell differentiation, while haploinsufficiency of DYRK1A is associated with severe microcephaly. Using a set of known and newly synthesized DYRK1A inhibitors, along with CRISPR-mediated gene activation and shRNA knockdown of DYRK1A, we show here that chemical inhibition or genetic knockdown of DYRK1A interferes with neural specification of human pluripotent stem cells, a process equating to the earliest stage of human brain development. Specifically, DYRK1A inhibition insulates the self-renewing subpopulation of human pluripotent stem cells from powerful signals that drive neural induction. Our results suggest a novel mechanism for the disruptive effects of the absence or haploinsufficiency of DYRK1A on early mammalian development, and reveal a requirement for DYRK1A in the acquisition of competence for differentiation in human pluripotent stem cells.

引用

页数：20

共 38 条

[1] DYRK1A in neurodegeneration and cancer: Molecular basis and clinical implications [J].

Abbassi, Ramzi ;

Johns, Terrance G. ;

Kassiou, Michael ;

Munoz, Lenka .

PHARMACOLOGY & THERAPEUTICS, 2015, 151 :87-98

[2] DYRK family of protein kinases: evolutionary relationships, biochemical properties, and functional roles [J].

Aranda, Sergi ;

Laguna, Ariadna ;

de la Luna, Susana .

FASEB JOURNAL, 2011, 25 (02) :449-462

[3] Alterations in the phenotype of neocortical pyramidal cells in the Dyrk1A+/- mouse [J].

Benavides-Piccione, R ;

Dierssen, M ;

Ballesteros-Yáñez, I ;

de Lagrán, MM ;

Arbonés, ML ;

Fotaki, V ;

DeFelipe, J ;

Elston, GN .

NEUROBIOLOGY OF DISEASE, 2005, 20 (01) :115-122

[4] Concise Review: Control of Cell Fate Through Cell Cycle and Pluripotency Networks [J].

Boward, Ben ;

Wu, Tianming ;

Dalton, Stephen .

STEM CELLS, 2016, 34 (06) :1427-1436

[5] Integration-Free Induced Pluripotent Stem Cells Model Genetic and Neural Developmental Features of Down Syndrome Etiology [J].

Briggs, James A. ;

Sun, Jane ;

Shepherd, Jill ;

Ovchinnikov, Dmitry A. ;

Chung, Tung-Liang ;

Nayler, Sam P. ;

Kao, Li-Pin ;

Morrow, Carl A. ;

Thakar, Nilay Y. ;

Soo, Set-Yen ;

Peura, Teija ;

Grimmond, Sean ;

Wolvetang, Ernst J. .

STEM CELLS, 2013, 31 (03) :467-478

[6] Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A [J].

Bronicki, Lucas M. ;

Redin, Claire ;

Drunat, Severine ;

Piton, Amelie ;

Lyons, Michael ;

Passemard, Sandrine ;

Baumann, Clarisse ;

Faivre, Laurence ;

Thevenon, Julien ;

Riviere, Jean-Baptiste ;

Isidor, Bertrand ;

Gan, Grace ;

Francannet, Christine ;

Willems, Marjolaine ;

Gunel, Murat ;

Jones, Julie R. ;

Gleeson, Joseph G. ;

Mandel, Jean-Louis ;

Stevenson, Roger E. ;

Friez, Michael J. ;

Aylsworth, Arthur S. .

EUROPEAN JOURNAL OF HUMAN GENETICS, 2015, 23 (11) :1482-1487

[7] DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome [J].

Canzonetta, Claudia ;

Mulligan, Claire ;

Deutsch, Samuel ;

Ruf, Sandra ;

O'Doherty, Aideen ;

Lyle, Robert ;

Borel, Christelle ;

Lin-Marq, Nathalie ;

Delom, Frederic ;

Groet, Juergen ;

Schnappauf, Felix ;

De Vita, Serena ;

Averill, Sharon ;

Priestley, John V. ;

Martin, Joanne E. ;

Shipley, Janet ;

Denyer, Gareth ;

Epstein, Charles J. ;

Fillat, Cristina ;

Estivill, Xavier ;

Tybulewicz, Victor L. J. ;

Fisher, Elizabeth M. C. ;

Antonarakis, Stylianos E. ;

Nizetic, Dean .

AMERICAN JOURNAL OF HUMAN GENETICS, 2008, 83 (03) :388-400

[8]

Chambers SM, 2016, METHODS MOL BIOL, V1307, P329, DOI 10.1007/7651_2013_59

[9] Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling [J].

Chambers, Stuart M. ;

Fasano, Christopher A. ;

Papapetrou, Eirini P. ;

Tomishima, Mark ;

Sadelain, Michel ;

Studer, Lorenz .

NATURE BIOTECHNOLOGY, 2009, 27 (03) :275-280

[10] A method for genetic modification of human embryonic stem cells using electroporation [J].

Costa, Magdaline ;

Dottori, Mirella ;

Sourris, Koula ;

Jamshidi, Pegah ;

Hatzistavrou, Tanya ;

Davis, Richard ;

Azzola, Lisa ;

Jackson, Steven ;

Lim, Sue Mei ;

Pera, Martin ;

Elefanty, Andrew G. ;

Stanley, Edouard G. .

NATURE PROTOCOLS, 2007, 2 (04) :792-796

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