Widespread failure of hematolymphoid differentiation caused by a recessive niche-filling allele of the Ikaros transcription factor.
A central issue in understanding the hematolymphoid system is the generation of appropriate mutant alleles in mice to reveal the function of regulatory genes. Here we describe a mouse strain, Plastic, with a point mutation in a zinc finger of Ikaros that disrupts DNA binding but preserves efficient assembly of the full-length protein into higher order complexes. Ikaros(Plastic) homozygosity is embryonically lethal with severe defects in terminal erythrocyte and granulocyte differentiation, excessive macrophage formation, and blocked lymphopoiesis, while heterozygotes display a partial block in lymphocyte differentiation. The contrast with more circumscribed effects of Ikaros alleles that ablate the full-length protein highlights the importance in mammals of generating recessive niche-filling alleles that inactivate function without creating a void in multimolecular assemblies.
Papathanasiou
Peter
P
Australian Cancer Research Foundation Genetics Laboratory and Medical Genome Centre, John Curtin School of Medical Research, Australian National University, ACT 2601, Canberra, Australia.
Perkins
Andrew C
AC
Cobb
Bradley S
BS
Ferrini
Roger
R
Sridharan
Rupa
R
Hoyne
Gerard F
GF
Nelms
Keats A
KA
Smale
Stephen T
ST
Goodnow
Christopher C
CC
D000483:Alleles; D000740:Anemia / Q000209:etiology; D000818:Animals; D002454:Cell Differentiation; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D019281:Dimerization; D004912:Erythrocytes / Q000502:physiology; D005038:Ethylnitrosourea; D006410:Hematopoiesis / Q000502:physiology*; D022781:Hepatocytes / Q000502:physiology; D051740:Ikaros Transcription Factor; D008214:Lymphocytes / Q000502:physiology; D008223:Lymphoma / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000502:physiology; D017354:Point Mutation; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D014157:Transcription Factors; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D004247:DNA; D005038:Ethylnitrosourea