Essential role of c-myb in definitive hematopoiesis is evolutionarily conserved.
The transcription factor c-myb has emerged as one of the key regulators of vertebrate hematopoiesis. In mice, it is dispensable for primitive stages of blood cell development but essentially required for definitive hematopoiesis. Using a conditional knock-out strategy, recent studies have indicated that c-myb is required for self-renewal of mouse hematopoietic stem cells. Here, we describe and characterize the c-myb mutant in a lower vertebrate, the zebrafish Danio rerio. The recessive loss-of-function allele of c-myb (c-myb(t25127)) was identified in a collection of N-ethyl-N-nitrosourea (ENU)-induced mutants exhibiting a failure of thymopoiesis. The sequence of the mutant allele predicts a missense mutation (I181N) in the middle of the DNA recognition helix of repeat 3 of the highly conserved DNA binding domain. In keeping with the findings in the mouse, primitive hematopoiesis is not affected in the c-myb mutant fish. By contrast, definitive hematopoiesis fails, resulting in the loss of all blood cells by day 20 of development. Thus, the mutant fish lack lymphocytes and other white and red blood cells; nonetheless, they survive for 2-3 mo but show stunted growth. Because the mutant fish survive into early adulthood, it was possible to directly show that their definitive hematopoiesis is permanently extinguished. Our results, therefore, suggest that the key role of c-myb in definitive hematopoiesis is similar to that in mammals and must have become established early in vertebrate evolution.
Soza-Ried
Cristian
C
Department of Developmental Immunology, Max-Planck Institute of Immunobiology, D-79108 Freiburg, Germany.
Hess
Isabell
I
Netuschil
Nikolai
N
Schorpp
Michael
M
Boehm
Thomas
T
D000818:Animals; D030801:Animals, Genetically Modified; D005075:Biological Evolution; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology; D017403:In Situ Hybridization; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011487:Protein Conformation; D020598:Proto-Oncogene Proteins c-myb / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013950:Thymus Gland / Q000033:anatomy & histology / Q000502:physiology; D015027:Zebrafish / Q000033:anatomy & histology / Q000235:genetics / Q000502:physiology
D020598:Proto-Oncogene Proteins c-myb
Nat Immunol. 2003 Dec;4(12):1238-46
14608381
Development. 1999 Sep;126(17):3735-45
10433904
Dev Biol. 2003 Mar 1;255(1):48-61
12618133
Cell. 1994 Nov 18;79(4):639-48
7954830
Oncogene. 2004 Sep 20;23(43):7233-46
15378083
Genes Dev. 1999 May 1;13(9):1073-8
10323859
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3829-34
17360438
Cell. 1982 Dec;31(2 Pt 1):453-63
6297766
Nat Genet. 1998 Nov;20(3):244-50
9806542
Cell. 2008 Feb 22;132(4):631-44
18295580
Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10713-7
7479870
Dev Biol. 2010 Sep 15;345(2):133-43
20621080
Development. 2007 Dec;134(23):4147-56
17959717
Blood. 1997 Jan 15;89(2):688-700
9002973
Development. 2008 May;135(10):1853-62
18417622
Semin Immunol. 2008 Aug;20(4):247-56
18585056
Cell. 2009 Jul 10;138(1):186-97
19559469
Blood. 2005 May 1;105(9):3480-7
15665109
Blood. 2009 Jun 4;113(23):5776-82
19332767
Nature. 2010 Mar 4;464(7285):112-5
20154732
J Immunol. 2006 Aug 15;177(4):2463-76
16888008
Genetics. 2005 Jan;169(1):215-29
15489525
Nature. 2010 Mar 4;464(7285):108-11
20154733
Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21689-94
19955420
Nature. 2010 Mar 4;464(7285):116-20
20154729
Blood. 2008 Feb 1;111(3):1147-56
17934068
Oncogene. 2000 Jul 13;19(30):3335-42
10918590
Blood. 2009 Dec 10;114(25):5162-72
19843882
Dev Cell. 2005 Feb;8(2):153-66
15691758
Methods. 2001 Apr;23(4):345-58
11316436
Cell. 1991 May 17;65(4):677-89
1709592