Nfe2 is dispensable for early but required for adult thrombocyte formation and function in zebrafish.

Autor:	Rost MS; Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI., Shestopalov I; Boston Children's Hospital and Harvard Medical School, Boston, MA., Liu Y; Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI., Vo AH; Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI., Richter CE; Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI., Emly SM; Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI., Barrett FG; Boston Children's Hospital and Harvard Medical School, Boston, MA., Stachura DL; Department of Biological Sciences, California State University Chico, Chico, CA., Holinstat M; Department of Pharmacology, University of Michigan, Ann Arbor, MI; and., Zon LI; Boston Children's Hospital and Harvard Medical School, Boston, MA.; Stem Cell Program and Division of Hematology/Oncology, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Dana-Farber Cancer Institute and Howard Hughes Medical Institute, Boston, MA., Shavit JA; Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2018 Dec 11; Vol. 2 (23), pp. 3418-3427.
DOI:	10.1182/bloodadvances.2018021865
Abstrakt:	The NFE2 transcription factor is expressed in multiple hematopoietic lineages with a well-defined role in regulating megakaryocyte biogenesis and platelet production in mammals. Mice deficient in NFE2 develop severe thrombocytopenia with lethality resulting from neonatal hemorrhage. Recent data in mammals reveal potential differences in embryonic and adult thrombopoiesis. Multiple studies in zebrafish have revealed mechanistic insights into hematopoiesis, although thrombopoiesis has been less studied. Rather than platelets, zebrafish possess thrombocytes, which are nucleated cells with similar functional properties. Using transcription activator-like effector nucleases to generate mutations in nfe2 , we show that unlike mammals, zebrafish survive to adulthood in the absence of Nfe2. Despite developing severe thrombocytopenia, homozygous mutants do not display overt hemorrhage or reduced survival. Surprisingly, quantification of circulating thrombocytes in mutant 6-day-old larvae revealed no significant differences from wild-type siblings. Both wild-type and nfe2 null larvae formed thrombocyte-rich clots in response to endothelial injury. In addition, ex vivo thrombocytic colony formation was intact in nfe2 mutants, and adult kidney marrow displayed expansion of hematopoietic progenitors. These data suggest that loss of Nfe2 results in a late block in adult thrombopoiesis, with secondary expansion of precursors: features consistent with mammals. Overall, our data suggest parallels with erythropoiesis, including distinct primitive and definitive pathways of development and potential for a previously unknown Nfe2-independent pathway of embryonic thrombopoiesis. Long-term homozygous mutant survival will facilitate in-depth study of Nfe2 deficiency in vivo, and further investigation could lead to alternative methodologies for the enhancement of platelet production. (© 2018 by The American Society of Hematology.)
Databáze:	MEDLINE
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