Abstract
A genomic variant in the human ADTRP [androgen-dependent tissue factor (TF) pathway inhibitor (TFPI) regulating protein] gene increases the risk of coronary artery disease, the leading cause of death worldwide. TFPI is the TF pathway inhibitor that is involved in coagulation. Here, we report that adtrp and tfpi form a regulatory axis that specifies primitive myelopoiesis and definitive hematopoiesis, but not primitive erythropoiesis or vasculogenesis. In zebrafish, there are 2 paralogues for adtrp (i.e., adtrp1 and adtrp2). Knockdown of adtrp1 expression inhibits the specification of hemangioblasts, as shown by decreased expression of the hemangioblast markers, etsrp, fli1a, and scl; blocks primitive hematopoiesis, as shown by decreased expression of pu.1, mpo, and l-plastin; and disrupts the specification of hematopoietic stem cells (definitive hematopoiesis), as shown by decreased expression of runx1 and c-myb. However, adtrp1 knockdown does not affect erythropoiesis during primitive hematopoiesis (no effect on gata1 or h-bae1) or vasculogenesis (no effect on kdrl, ephb2a, notch3, dab2, or flt4). Knockdown of adtrp2 expression does not have apparent effects on all markers tested. Knockdown of adtrp1 reduced the expression of tfpi, and hematopoietic defects in adtrp1 morphants were rescued by tfpi overexpression. These data suggest that the regulation of tfpi expression is one potential mechanism by which adtrp1 regulates primitive myelopoiesis and definitive hematopoiesis.Wang, L.,Wang, X.,Wang, L.,Yousaf,M.,Li, J.,Zuo,M.,Yang,Z.,Gou,D., Bao, B., Li,L., Xiang,N., Jia,H.,Xu,C.,Chen,Q.,Wang,Q.K.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 183-194 |
| Number of pages | 12 |
| Journal | FASEB Journal |
| Volume | 32 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2018 |
| Externally published | Yes |
Bibliographical note
Funding Information:This work was supported by the China National Natural Science Foundation (Grants 31430047, 81630003, and 91439129), Chinese National Basic Research (973 Programs 2013CB531101 and 2012CB517801), Hubei Province’s Outstanding Medical Academic Leader Program, Hubei Province Natural Science Programs (2016CFB224 and 2014CFA074), and the U.S. National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (Grants R01-HL121358 and R01-HL126729). Other related research projects on ADTRP in the Q.K.W. Laboratory received funding from Bayer Health.
Funding Information:
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology, Center for Human Genome Research, and †Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; ‡Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, and §Department of Molecular Medicine, Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio, USA; and {Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, USA This work was supported by the China National Natural Science Foundation (Grants 31430047, 81630003, and 91439129), Chinese National Basic Research (973 Programs 2013CB531101 and 2012CB517801), Hubei Province’s Outstanding Medical Academic Leader Program, Hubei Province Natural Science Programs (2016CFB224 and 2014CFA074), and the U.S. National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (Grants R01-HL121358 and R01-HL126729). Other related research projects on ADTRP in the Q.K.W. Laboratory received funding from Bayer Health.
Publisher Copyright:
© FASEB.
Keywords
- Aggf1
- Coagulation
- Hemangioblasts
- Vascular development
