NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network

被引：82

作者：

Anderson, David J. ^{[1
]}

Kaplan, David I. ^{[2
,3
]}

Bell, Katrina M. ^{[1
]}

Koutsis, Katerina ^{[1
]}

Haynes, John M. ^{[4
]}

Mills, Richard J. ^{[5
]}

Phelan, Dean G. ^{[1
]}

Qian, Elizabeth L. ^{[1
]}

Leitoguinho, Ana Rita ^{[1
]}

Arasaratnam, Deevina ^{[1
]}

Labonne, Tanya ^{[1
]}

Ng, Elizabeth S. ^{[1
]}

Davis, Richard P. ^{[6
]}

Casini, Simona ^{[6
]}

Passier, Robert ^{[6
]}

Hudson, James E. ^{[5
]}

Porrello, Enzo R. ^{[5
]}

Costa, Mauro W. ^{[7
]}

Rafii, Arash ^{[8
,9
]}

Curl, Clare L. ^{[10
]}

Delbridge, Lea M. ^{[10
]}

Harvey, Richard P. ^{[11
,12
,13
]}

Oshlack, Alicia ^{[1
]}

Cheung, Michael M. ^{[1
,14
]}

Mummery, Christine L. ^{[6
]}

Petrou, Stephen ^{[2
,3
]}

Elefanty, Andrew G. ^{[1
,14
,15
]}

Stanley, Edouard G. ^{[1
,14
,15
]}

Elliott, David A. ^{[1
,16
,17
]}

机构：

[1] Royal Childrens Hosp, Murdoch Childrens Res Inst, Flemington Rd, Parkville, Vic 3052, Australia

[2] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3052, Australia

[3] Univ Melbourne, Ctr Neurosci, Parkville, Vic 3052, Australia

[4] Monash Univ, Monash Inst Pharmaceut Sci, 381 Royal Parade Parkville, Parkville, Vic 3052, Australia

[5] Univ Queensland, Sch Biomed Sci, Brisbane, Qld 4072, Australia

[6] Leiden Univ, Med Ctr, Dept Anat & Embryol, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands

[7] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA

[8] Qatar Fdn, Weill Cornell Med Coll Qatar, Stem Cell & Microenvironm Lab, Doha, Qatar

[9] Weill Cornell Med Coll, Dept Genet Med, New York, NY USA

[10] Univ Melbourne, Dept Physiol, Parkville, Vic 3052, Australia

[11] Victor Chang Cardiac Res Inst, Darlinghurst, NSW 2052, Australia

[12] Univ New South Wales, St Vincents Clin Sch, Kensington, NSW 2052, Australia

[13] Univ New South Wales, Sch Biotechnol & Biomol Sci, Kensington, NSW 2052, Australia

[14] Univ Melbourne, Dept Pediat, Royal Childrens Hosp, Parkville, Vic 3052, Australia

[15] Monash Univ, Dept Anat & Dev Biol, Fac Med Nursing & Hlth Sci, Clayton, Vic 3800, Australia

[16] Monash Univ, Australian Regenerat Med Inst, Clayton, Vic 3800, Australia

[17] Univ Melbourne, Sch Biosci, Parkville, Vic 3052, Australia

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

英国医学研究理事会; 澳大利亚研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

PLURIPOTENT STEM-CELLS; CONGENITAL HEART-DEFECTS; GENE-EXPRESSION; MOUSE MODEL; DISEASE; PROGENITORS; REPRESSION; MUTATIONS; ACTIVATION; MECHANISM;

D O I：

10.1038/s41467-018-03714-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Congenital heart defects can be caused by mutations in genes that guide cardiac lineage formation. Here, we show deletion of NKX2-5, a critical component of the cardiac gene regulatory network, in human embryonic stem cells (hESCs), results in impaired cardiomyogenesis, failure to activate VCAM1 and to downregulate the progenitor marker PDGFR alpha. Furthermore, NKX2-5 null cardiomyocytes have abnormal physiology, with asynchronous contractions and altered action potentials. Molecular profiling and genetic rescue experiments demonstrate that the bHLH protein HEY2 is a key mediator of NKX2-5 function during human cardiomyogenesis. These findings identify HEY2 as a novel component of the NKX2-5 cardiac transcriptional network, providing tangible evidence that hESC models can decipher the complex pathways that regulate early stage human heart development. These data provide a human context for the evaluation of pathogenic mutations in congenital heart disease.

引用

页数：13

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