Control of thymocyte development and recombination-activating gene expression by the zinc finger protein Zfp608.
The products of recombination-activating gene 1 (Rag1) and Rag2 are required for T cell receptor gene assembly and thymocyte maturation, yet their transcriptional control mechanisms remain unclear. A congenic strain (called 'ZORI' here) with defects in Rag1 and Rag2 expression, thymocyte maturation and peripheral T cell homeostasis has been developed. Here, we mapped the mutation in this strain to a chromosome 18 locus containing a single known gene encoding the zinc finger protein Zfp608. This gene (Zfp608) was highly expressed in neonatal thymus but was extinguished thereafter. In contrast to wild-type mice, ZORI mice had sustained thymocyte expression of Zfp608 throughout life. The ZORI mutation produced a thymocyte-intrinsic developmental defect. Overexpression of Zfp608 in BALB/c thymocytes substantially impaired Rag1 and Rag2 expression, indicating the underlying mechanism for the defect in ZORI thymocyte development. Thus, the normal function of Zfp608 may be to prevent Rag1 and Rag2 expression in utero.
Zhang
Feng
F
Division of Rheumatology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Thomas
Lance R
LR
Oltz
Eugene M
EM
Aune
Thomas M
TM
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D016654:Genes, RAG-1 / Q000502:physiology*; D015151:Immunoblotting; D017403:In Situ Hybridization; D008214:Lymphocytes / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D020297:Mice, Congenic; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013950:Thymus Gland / Q000196:embryology*; D016335:Zinc Fingers / Q000276:immunology*
D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse