Proplatelet formation of megakaryocytes is triggered by autocrine-synthesized estradiol.
A matured megakaryocyte releases thousands of platelets through a drastic morphological change, proplatelet formation (PPF). The megakaryocyte/erythrocyte-specific transcription factor, p45 NF-E2, is essential for initiating PPF, but the factor regulating PPF has not been identified. Here we report that estradiol synthesized in megakaryocytes triggers PPF. We demonstrate that a key enzyme for steroid hormone biosynthesis, 3beta-hydroxysteroid dehydrogenase (3beta-HSD), is a target of p45 NF-E2, and rescues PPF of p45 NF-E2-deficient megakaryocytes. We also show that estradiol is synthesized within megakaryocytes, and that extracellular estradiol stimulates PPF, inhibition of 3beta-HSD activity blocks PPF, and estrogen receptor antagonists inhibit platelet production in vivo. We conclude that autocrine estradiol action regulates platelet production by triggering PPF.
Nagata
Yuka
Y
Recognition and Formation, Precursory Research for Embryonic Science and Technology, Japan Science and Technology Corporation, Japan. y-nagata@postman.riken.go.jp
Yoshikawa
Jun
J
Hashimoto
Atsushi
A
Yamamoto
Masayuki
M
Payne
Anita H
AH
Todokoro
Kazuo
K
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001792:Blood Platelets / Q000166:cytology*; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D050981:Erythroid-Specific DNA-Binding Factors; D004958:Estradiol / Q000502:physiology*; D007150:Immunohistochemistry; D008533:Megakaryocytes / Q000166:cytology*; D051379:Mice; D008969:Molecular Sequence Data; D050983:NF-E2 Transcription Factor; D050984:NF-E2 Transcription Factor, p45 Subunit; D014157:Transcription Factors / Q000378:metabolism
D017931:DNA Primers; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D050981:Erythroid-Specific DNA-Binding Factors; D050983:NF-E2 Transcription Factor; D050984:NF-E2 Transcription Factor, p45 Subunit; C494693:Nfe2 protein, mouse; D014157:Transcription Factors; D004958:Estradiol; D015096:3-Hydroxysteroid Dehydrogenases