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Haematologica 2019 Volume 104(10):1984-1994
Red Cell Biology and its Disorders
Deletion of a flippase subunit Tmem30a in hematopoietic cells impairs mouse fetal liver erythropoiesis
Fan Yang,1* Yumin Huang,2* Xianda Chen,1* Lu Liu,1 Dandan Liao,1 Huan Zhang,3,4 Gang Huang,5 Wenjing Liu,6 Xianjun Zhu,6,7 Wengong Wang,8 Cheryl A. Lobo,9 Karina Yazdanbakhsh,10 Xiuli An2,3,4 and Zhenyu Ju1,11
1Key Laboratory of Regenerative Medicine of Ministry of Education, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, China; 2Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; 3Laboratory of Membrane Biology, New York Blood Center, New York, NY, USA; 4School of Life Science, Zhengzhou University, Zhengzhou, China; 5Division of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 6The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Institute of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China and Chengdu, Sichuan, China; 7Chengdu Institute of Biology, Sichuan Translational Medicine Research Hospital, Chinese Academy of Sciences, Chengdu, China; 8Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; 9Laboratory of Blood-Borne Parasites, New York Blood Center, New York, NY, USA; 10Laboratory of Complement Biology, New York Blood Center, New York, NY, USA and 11Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China
*FY, YH and XC contributed equally to this work.
ABSTRACT
Transmembrane protein 30A (Tmem30a) is the β-subunit of P4- ATPases which function as flippase that transports aminophospho- lipids such as phosphatidylserine from the outer to the inner leaflets of the plasma membrane to maintain asymmetric distribution of phospho- lipids. It has been documented that deficiency of Tmem30a led to exposure of phosphatidylserine. However, the role of Tmem30a in vivo remains largely unknown. Here we found that Vav-Cre-driven conditional deletion of Tmem30a in hematopoietic cells led to embryonic lethality due to severe anemia by embryonic day 16.5. The numbers of erythroid colonies and ery- throid cells were decreased in the Tmem30a deficient fetal liver. This was accompanied by increased apoptosis of erythroid cells. Confocal microscopy analysis revealed an increase of localization of erythropoietin receptor to areas of membrane raft microdomains in response to erythro- poietin stimulation in Ter119– erythroid progenitors, which was impaired in Tmem30a deficient cells. Moreover, erythropoietin receptor (EPOR)-mediat- ed activation of the STAT5 pathway was significantly reduced in Tmem30a deficient fetal liver cells. Consistently, knockdown of TMEM30A in human CD34+ cells also impaired erythropoiesis. Our findings demonstrate that Tmem30a plays a critical role in erythropoiesis by regulating the EPOR sig- naling pathway through the formation of membrane rafts in erythroid cells.
Introduction
Hematopoietic stem cells (HSC) are long lived and able to differentiate into sev- eral lineages which are required throughout life.1 There are two distinct waves of hematopoietic cells during mammalian embryogenesis. The first wave progenitors arise in the circulation of the yolk sac (YS) at embryonic day 7.25 (E7.25), and pro- duce primitive erythrocytes which are essential for the survival of the embryo. The second wave HSC arise at embryonic day 10.5 in the dorsal aorta and differentiate
Correspondence:
ZHENYU JU
zhenyuju@163.com
XIULI AN
xan@nybc.org
Received: August 7, 2018. Accepted: February 27, 2019. Pre-published: February 28, 2019.
doi:10.3324/haematol.2018.203992
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