Hemp, an mbt domain-containing protein, plays essential roles in hematopoietic stem cell function and skeletal formation.
To clarify the molecular pathways governing hematopoietic stem cell (HSC) development, we screened a fetal liver (FL) HSC cDNA library and identified a unique gene, hematopoietic expressed mammalian polycomb (hemp), encoding a protein with a zinc-finger domain and four malignant brain tumor (mbt) repeats. To investigate its biological role, we generated mice lacking Hemp (hemp(-/-)). Hemp(-/-) mice exhibited a variety of skeletal malformations and died soon after birth. In the FL, hemp was preferentially expressed in the HSC and early progenitor cell fractions, and analyses of fetal hematopoiesis revealed that the number of FL mononuclear cells, including HSCs, was reduced markedly in hemp(-/-) embryos, especially during early development. In addition, colony-forming and competitive repopulation assays demonstrated that the proliferative and reconstitution abilities of hemp(-/-) FL HSCs were significantly impaired. Microarray analysis revealed alterations in the expression levels of several genes implicated in hematopoietic development and differentiation in hemp(-/-) FL HSCs. These results demonstrate that Hemp, an mbt-containing protein, plays essential roles in HSC function and skeletal formation. It is also hypothesized that Hemp might be involved in certain congenital diseases, such as Klippel-Feil anomaly.
Department of Disease Model, Research Institute of Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima 734-8553, Japan. hhonda@hiroshima-u.ac.jp
Hiroaki
H
Honda
Keiyo
K
Takubo
Hideaki
H
Oda
Kenjiro
K
Kosaki
Tatsuya
T
Tazaki
Norimasa
N
Yamasaki
Kazuko
K
Miyazaki
Kateri A
KA
Moore
Zen-ichiro
Z
Honda
Toshio
T
Suda
Ihor R
IR
Lemischka
D000818:Animals; D001846:Bone Development / Q000502:physiology*; D001842:Bone and Bones / Q000196:embryology*; D002454:Cell Differentiation / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006410:Hematopoiesis / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007714:Klippel-Feil Syndrome / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
D002868:Chromosomal Proteins, Non-Histone; D012097:Repressor Proteins; C556963:hemp protein, mouse
Gene. 2003 Nov 13;319:117-26
14597177
FEBS Lett. 2001 Oct 19;507(1):119-21
11682070
Cell. 2007 Jun 1;129(5):915-28
17540172
Mol Cell Biol. 1997 Nov;17(11):6683-92
9343432
Int J Hematol. 2001 Jul;74(1):9-17
11530812
Nat Struct Mol Biol. 2007 Dec;14(12):1229-30
18026117
Science. 1996 Jul 12;273(5272):242-5
8662508
Curr Opin Genet Dev. 2006 Oct;16(5):496-501
16919448
Nature. 1996 Apr 25;380(6576):711-4
8614465
Mech Dev. 1995 Sep;53(1):141-54
8555106
Gene. 1999 Sep 3;237(1):185-91
10524249
Clin Dysmorphol. 2003 Jul;12(3):197
14564161
Science. 2000 Jun 2;288(5471):1635-40
10834841
EMBO J. 2009 Jul 8;28(13):1965-77
19494831
Clin Orthop Relat Res. 1969 Nov-Dec;67:105-10
5361187
Genomics. 1999 May 15;58(1):65-72
10331946
Stem Cells. 2001;19(5):378-87
11553846
Genes Dev. 1994 Apr 1;8(7):757-69
7926765
Development. 1996 May;122(5):1621-30
8625848
Blood. 2006 Jul 15;108(2):737-44
16569764
Am J Med Genet. 1995 Jul 3;57(3):447-9
7677149
Clin Pediatr (Phila). 1984 Sep;23(9):520-1
6467789
Gene. 2000 May 2;248(1-2):127-35
10806358
Eur J Hum Genet. 2007 May;15(5):570-7
17327879
Cell Mol Life Sci. 1998 Jan;54(1):71-9
9487388
Nature. 1996 Jul 11;382(6587):174-7
8700209
Eur J Med Genet. 2008 Jan-Feb;51(1):74-80
18024240
Genes Dev. 2006 May 1;20(9):1110-22
16618800
Am J Med Genet A. 2009 Jun;149A(6):1257-62
19449402
Eur J Immunol. 1997 May;27(5):1292-5
9174623
Childs Nerv Syst. 2008 Oct;24(10):1123-45
18461336
Nat Immunol. 2007 Jan;8(1):84-91
17115060
Am J Med Genet A. 2006 May 1;140(9):1013-5
16575895
Front Biosci (Landmark Ed). 2009 Jun 01;14:5273-90
19482615
Development. 1996 May;122(5):1513-22
8625838
Cell. 2009 Apr 17;137(2):369-79
19379700
EMBO J. 2005 May 18;24(10):1863-73
15889154
Blood. 2010 Jul 29;116(4):544-53
20442369
Cytokine. 2004 Jun 21;26(6):231-42
15183840
Nucleic Acids Res. 2009 Apr;37(7):2204-10
19233876
Nature. 2008 May 15;453(7193):306-13
18480811
Bull Hosp Jt Dis Orthop Inst. 1991 Spring;51(1):54-62
1652319
Blood. 2007 Dec 1;110(12):3968-77
17712048
Blood. 2006 Feb 15;107(4):1357-65
16234353
Oncogene. 1999 Jul 1;18(26):3799-809
10445843
EMBO Rep. 2006 Apr;7(4):397-403
16415788
Blood. 2000 Nov 1;96(9):3209-14
11050005
Development. 1997 Feb;124(3):721-9
9043087
Nat Immunol. 2008 Feb;9(2):129-36
18204427
Cell. 1986 Jun 20;45(6):917-27
2871944
Neurosurg Clin N Am. 2007 Jul;18(3):463-78
17678749