Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse

@article{Brunkow2001DisruptionOA,
  title={Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse},
  author={Mary E. Brunkow and Eric W. Jeffery and Kathryn A. Hjerrild and Bryan Paeper and L B Clark and Sue-Ann Yasayko and John Erby Wilkinson and David J. Galas and Steven F. Ziegler and Fred Ramsdell},
  journal={Nature Genetics},
  year={2001},
  volume={27},
  pages={68-73}
}
Scurfy (sf) is an X-linked recessive mouse mutant resulting in lethality in hemizygous males 16–25 days after birth, and is characterized by overproliferation of CD4+CD8– T lymphocytes, extensive multiorgan infiltration and elevation of numerous cytokines. Similar to animals that lack expression of either Ctla-4 (refs. 5,6) or Tgf-β (refs. 7,8), the pathology observed in sf mice seems to result from an inability to properly regulate CD4+CD8– T-cell activity. Here we identify the gene defective… 
Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease
TLDR
Experimental evidence that the absence of Foxp3+ T reg cells is indeed sufficient to induce a scurfy-like phenotype is provided, and the generation of DEREG mice will allow a more precise definition of the function of Fox p3+T reg cells in immune reactions in vivo.
The Amount of Scurfin Protein Determines Peripheral T Cell Number and Responsiveness1
TLDR
A critical role for the Foxp3 gene product in the function of the immune system is indicated, with both the number and functionality of peripheral T cells under the aegis of the scurfin protein.
Scurfin (FOXP3) Acts as a Repressor of Transcription and Regulates T Cell Activation*
TLDR
The findings indicate that the ability of scurfin to bind DNA, and presumably repress transcription, plays a paramount role in determining the amplitude of the response of CD4 T cells to activation.
Analysis of FOXP3 Reveals Multiple Domains Required for Its Function as a Transcriptional Repressor1
TLDR
It is shown that FOXP3 is constitutively localized to the nucleus and this localization requires sequences at both the amino and C-terminal ends of its FKH domain, which was found to homodimerize through its leucine zipper.
The medaka FoxP2, a homologue of human language gene FOXP2, has a diverged structure and function.
TLDR
Results suggest that medaka FoxP2 may play a different function in the development of the medaka fish, after it was found that the three amino acids of forkhead domain were responsible for the weak repressive activity.
The Scurfy mutation of FoxP3 in the thymus stroma leads to defective thymopoiesis
TLDR
The data reveal a novel T cell–extrinsic function of FoxP3 and provide plausible explanation for the severity of the autoimmune diseases in the scurfy mice and in patients who have immunodysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome.
Molecular cloning, characterization, and developmental expression of foxp1 in zebrafish
TLDR
Results of whole-mount in situ hybridization showed that foxp1 exhibits very complex and dynamic expression pattern during early embryonic development, providing evidence thatfoxp1 is likely to function as a very important transcription factor in the development of the central nervous system and many other organs in zebrafish.
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References

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TLDR
Flow cytometric analyses of lymphoid cell populations reveal that scurfy syndrome is characterized by changes in several phenotypic parameters, including an increase in Mac-1+ cells and a decrease in B220+ cells, changes that may result from the production of extremely high levels of the cytokine granulocyte-macrophage CSF by scurfi T cells.
Disease in the scurfy (sf) mouse is associated with overexpression of cytokine genes
TLDR
Overall, the phenotypic characteristics of scurfy disease correlated well with increased interleukin (IL)‐4 (lymphadenopathy), IL‐6 (B cell proliferation, hypergammaglobulinemia, IL‐7 (dermal inflammatory cell infiltration), and high levels of tumor necrosis factor‐α (wasting).
CD4+CD8- T cells are the effector cells in disease pathogenesis in the scurfy (sf) mouse.
Mice hemizygous for the X-linked mutation, scurfy (sf), exhibit a fatal lymphoreticular disease that is mediated by T lymphocytes. To evaluate the respective roles of CD4 or CD8 single positive T
Unified nomenclature for the winged helix/forkhead transcription factors.
The winged helix/forkhead class of transcription factors is characterized by a 100-amino-acid, monomeric DNAbinding domain. The structure of the DNA-binding domain of one of the class members,
The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles Wiskott-Aldrich syndrome.
The X chromosome-linked scurfy (sf) mutant of the mouse is recognized by the scaliness of the skin from which the name is derived and results in death of affected males at about 3-4 weeks of age.
Transplantation of T cell-mediated, lymphoreticular disease from the scurfy (sf) mouse.
TLDR
The findings indicate that scurfy disease can be transmitted to T cell-deficient mice by engraftment of scurFY T cells, but that pathogenic scurfi T cell activities can be inhibited (or prevented) in immunocompetent recipient mice.
Analysis of hepatocyte nuclear factor-3 beta protein domains required for transcriptional activation and nuclear targeting.
TLDR
It is demonstrated that activity of the HNF-3 N-terminal domain was diminished by mutations which altered a putative alpha-helical structure located between amino acid residues 14 and 19, and the nuclear localization signal overlaps with the winged helix DNA-binding motif.
A targeted mutation at the T-cell receptor alpha/delta locus impairs T-cell development and reveals the presence of the nearby antiapoptosis gene Dad1
TLDR
It is reported that the chromatin between TCR alpha and Dad1 is DNase I hypersensitive in a variety of cell types, thus correlating with Dad1 expression and raising the possibility that Dad1 regulatory sequences reside in this region.
A transcript map of a 2-Mb BAC contig in the proximal portion of the mouse X chromosome and regional mapping of the scurfy mutation.
TLDR
A physical clone contig has been constructed, spanning 2 Mb on the proximal mouse X chromosome containing the mouse scurfy and tattered mutations, and a number of genetic markers have been developed, which has enabled the region containing the sf mutation to be narrowed to <300 kb.
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