Zebrafish mll Gene Is Essential for Hematopoiesis

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	Zebrafish mll Gene Is Essential for Hematopoiesis
	Wan, Xiaoyang; Hu, Bo; Liu, Jing-xia; Feng, Xi; Xiao, Wuhan
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2011-09-23
卷号	286 期号:38 页码:33345-33357
关键词	PROTO-ONCOPROTEIN MLL HOX GENES ACUTE LEUKEMIAS STEM-CELL DEFINITIVE HEMATOPOIESIS DROSOPHILA-TRITHORAX 11Q23 TRANSLOCATIONS DNA DEMETHYLATION MUTANT MICE HISTONE
ISSN号	0021-9258
通讯作者	Xiao, WH (reprint author), Chinese Acad Sci, Inst Hydrobiol, Key Lab Aquat Biodivers & Conservat, Wuhan 430072, Peoples R China ; w-xiao@ihb.ac.cn
中文摘要	Studies implicate an important role for the mixed lineage leukemia (Mll) gene in hematopoiesis, mainly through maintaining Hox gene expression. However, the mechanisms underlying Mll-mediated hematopoiesis during embryogenesis remain largely unclear. Here, we investigate the role of mll during zebrafish embryogenesis, particularly hematopoiesis. Mll depletion caused severe defects in hematopoiesis as indicated by a lack of blood flow and mature blood cells as well as a significant reduction in expression of hematopoietic progenitor and mature blood cell markers. Furthermore, mll depletion prevented the differentiation of hematopoietic progenitors. In addition, we identified the N-terminal mini-peptide of Mll that acted as a dominant negative form to disrupt normal function of mll during embryogenesis. As expected, mll knockdown altered the expression of a subset of Hox genes. However, overexpression of these down-regulated Hox genes only partially rescued the blood deficiency, suggesting that mll may target additional genes to regulate hematopoiesis. In the mll morphants, microarray analysis revealed a dramatic up-regulation of gadd45 alpha a. Multiple assays indicate that mll inhibited gadd45 alpha a expression and that overexpression of gadd45 alpha a mRNA led to a phenotype similar to the one seen in the mll morphants. Taken together, these findings demonstrate that zebrafish mll plays essential roles in hematopoiesis and that gadd45 alpha a may serve as a potential downstream target for mediating the function of mll in hematopoiesis.
英文摘要	Studies implicate an important role for the mixed lineage leukemia (Mll) gene in hematopoiesis, mainly through maintaining Hox gene expression. However, the mechanisms underlying Mll-mediated hematopoiesis during embryogenesis remain largely unclear. Here, we investigate the role of mll during zebrafish embryogenesis, particularly hematopoiesis. Mll depletion caused severe defects in hematopoiesis as indicated by a lack of blood flow and mature blood cells as well as a significant reduction in expression of hematopoietic progenitor and mature blood cell markers. Furthermore, mll depletion prevented the differentiation of hematopoietic progenitors. In addition, we identified the N-terminal mini-peptide of Mll that acted as a dominant negative form to disrupt normal function of mll during embryogenesis. As expected, mll knockdown altered the expression of a subset of Hox genes. However, overexpression of these down-regulated Hox genes only partially rescued the blood deficiency, suggesting that mll may target additional genes to regulate hematopoiesis. In the mll morphants, microarray analysis revealed a dramatic up-regulation of gadd45 alpha a. Multiple assays indicate that mll inhibited gadd45 alpha a expression and that overexpression of gadd45 alpha a mRNA led to a phenotype similar to the one seen in the mll morphants. Taken together, these findings demonstrate that zebrafish mll plays essential roles in hematopoiesis and that gadd45 alpha a may serve as a potential downstream target for mediating the function of mll in hematopoiesis.
学科主题	Biochemistry & Molecular Biology
WOS标题词	Science & Technology ; Life Sciences & Biomedicine
类目[WOS]	Biochemistry & Molecular Biology
研究领域[WOS]	Biochemistry & Molecular Biology
关键词[WOS]	PROTO-ONCOPROTEIN MLL ; HOX GENES ; 11Q23 TRANSLOCATIONS ; ACUTE LEUKEMIAS ; STEM-CELL ; DEFINITIVE HEMATOPOIESIS ; DROSOPHILA-TRITHORAX ; DNA DEMETHYLATION ; MUTANT MICE ; HISTONE
收录类别	SCI
资助信息	National Science Foundation of China[30971667, 31071212, 91019008, 20890113]; National Transgene Project[2009ZX08010-021B]
语种	英语
WOS记录号	WOS:000294968800053
公开日期	2011-11-09
内容类型	期刊论文
源URL	[http://ir.ihb.ac.cn/handle/342005/16351]
专题	水生生物研究所_水生生物分子与细胞生物学研究中心_期刊论文
作者单位	Chinese Acad Sci, Inst Hydrobiol, Key Lab Aquat Biodivers & Conservat, Wuhan 430072, Peoples R China
推荐引用方式 GB/T 7714	Wan, Xiaoyang,Hu, Bo,Liu, Jing-xia,et al. Zebrafish mll Gene Is Essential for Hematopoiesis[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2011,286(38):33345-33357.
APA	Wan, Xiaoyang,Hu, Bo,Liu, Jing-xia,Feng, Xi,&Xiao, Wuhan.(2011).Zebrafish mll Gene Is Essential for Hematopoiesis.JOURNAL OF BIOLOGICAL CHEMISTRY,286(38),33345-33357.
MLA	Wan, Xiaoyang,et al."Zebrafish mll Gene Is Essential for Hematopoiesis".JOURNAL OF BIOLOGICAL CHEMISTRY 286.38(2011):33345-33357.