Inhibition of endothelial ERK signalling by Smad1/5 is essential for haematopoietic stem cell emergence

Chunxia Zhang; Junhua Lv; Qiuping He; Sifeng Wang; Ya Gao; Anming Meng; Xiao Yang; Feng Liu

doi:10.1038/ncomms4431

Inhibition of endothelial ERK signalling by Smad1/5 is essential for haematopoietic stem cell emergence

Nat Commun. 2014 Mar 11:5:3431. doi: 10.1038/ncomms4431.

Authors

Chunxia Zhang¹, Junhua Lv¹, Qiuping He¹, Sifeng Wang¹, Ya Gao¹, Anming Meng², Xiao Yang³, Feng Liu¹

Affiliations

¹ State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
² State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
³ State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing 100071, China.

PMID: 24614941
DOI: 10.1038/ncomms4431

Abstract

The earliest HSCs are derived from haemogenic endothelium via endothelial-to-haematopoietic transition during vertebrate embryogenesis; however, the underlying mechanism is largely unclear. Here we show that interplay of Smad1/5 and ERK signalling is essential for haemogenic endothelium-based HSC emergence. Smad1/5 directly inhibits erk expression through recruiting HDAC1 to and inducing de-acetylation of the erk promoter in endothelial cells. Over-activated ERK signalling conferred by inhibition of Smad1/5 promotes the arterial endothelial cell fate and constitutively strengthens the tight junction between endothelial cells, thereby repressing the specification of haemogenic endothelium and the following endothelial-to-haematopoietic transition process. These findings provide new insights into the in vitro generation of transplantable HSCs for potential clinical applications.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Genetically Modified
Blotting, Western
Embryo, Nonmammalian / cytology
Embryo, Nonmammalian / embryology
Embryo, Nonmammalian / metabolism*
Endothelial Cells / metabolism
Endothelial Cells / ultrastructure
Endothelium, Vascular / cytology
Endothelium, Vascular / embryology
Endothelium, Vascular / metabolism
Gene Expression Regulation, Developmental
Gene Knockdown Techniques
Hematopoiesis / genetics
Hematopoietic Stem Cells / metabolism*
Histone Deacetylase 1 / genetics
Histone Deacetylase 1 / metabolism
In Situ Hybridization
Luminescent Proteins / genetics
Luminescent Proteins / metabolism
MAP Kinase Signaling System / genetics*
Microscopy, Confocal
Microscopy, Electron, Transmission
Mitogen-Activated Protein Kinase 1 / genetics
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / genetics
Mitogen-Activated Protein Kinase 3 / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Smad1 Protein / genetics*
Smad1 Protein / metabolism
Smad5 Protein / genetics*
Smad5 Protein / metabolism
Zebrafish / embryology
Zebrafish / genetics
Zebrafish / metabolism
Zebrafish Proteins / genetics*
Zebrafish Proteins / metabolism

Substances

Luminescent Proteins
Smad1 Protein
Smad5 Protein
Zebrafish Proteins
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Histone Deacetylase 1