Mef2C is a lineage-restricted target of Scl/Tal1 and regulates megakaryopoiesis and B-cell homeostasis

被引：44

作者：

Gekas, Christos ^{[1
]}

Rhodes, Katrin E. ^{[1
]}

Gereige, Laurraine M. ^{[1
]}

Helgadottir, Hildur ^{[2
]}

Ferrari, Roberto ^{[3
]}

Kurdistani, Siavash K. ^{[3
]}

Montecino-Rodriguez, Encarnacion ^{[4
]}

Bassel-Duby, Rhonda ^{[5
]}

Olson, Eric ^{[5
]}

Krivtsov, Andrei V. ^{[6
]}

Armstrong, Scott ^{[2
,6
]}

Orkin, Stuart H. ^{[2
,6
,7
,8
]}

Pellegrini, Matteo ^{[1
,9
]}

Mikkola, Hanna K. A. ^{[1
,9
,10
,11
]}

机构：

[1] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[3] Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

[5] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA

[6] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Hematol Oncol, Cambridge, MA 02138 USA

[7] Howard Hughes Med Inst, Boston, MA 02115 USA

[8] Harvard Stem Cell Inst, Boston, MA USA

[9] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA

[10] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA 90095 USA

[11] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA

来源：

BLOOD | 2009年 / 113卷 / 15期

关键词：

TRANSCRIPTION FACTOR MEF2C; HEMATOPOIETIC STEM-CELLS; HELIX-LOOP-HELIX; MUSCLE DEVELOPMENT; GENE-EXPRESSION; MYOGENIC BHLH; FACTOR SCL; YOLK-SAC; ABSENCE; PRECURSORS;

D O I：

10.1182/blood-2008-07-167577

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The basic helix-loop-helix transcription factor stem cell leukemia gene (Scl) is a master regulator for hematopoiesis essential for hematopoietic specification and proper differentiation of the erythroid and megakaryocyte lineages. However, the critical downstream targets of Scl remain undefined. Here, we identified a novel Scl target gene, transcription factor myocyte enhancer factor 2 C (Mef2C) from Scl(fl/fl) fetal liver progenitor cell lines. Analysis of Mef2C(-/-) embryos showed that Mef2C, in contrast to Scl, is not essential for specification into primitive or definitive hematopoietic lineages. However, adult VavCre(+)Mef2C(fl/fl) mice exhibited platelet defects similar to those observed in Scl-deficient mice. The platelet counts were reduced, whereas platelet size was increased and the platelet shape and granularity were altered. Furthermore, megakaryopoiesis was severely impaired in vitro. Chromatin immunoprecipitation microarray hybridization analysis revealed that Mef2C is directly regulated by Scl in megakaryocytic cells, but not in erythroid cells. In addition, an Scl-independent requirement for Mef2C in B-lymphoid homeostasis was observed in Mef2C-deficient mice, characterized as severe age-dependent reduction of specific B-cell progenitor populations reminiscent of premature aging. In summary, this work identifies Mef2C as an integral member of hematopoietic transcription factors with distinct upstream regulatory mechanisms and functional requirements in megakaryocyte and B-lymphoid lineages. (Blood. 2009; 113: 3461-3471)

引用

页码：3461 / 3471

页数：11

共 22 条

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