Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 31, Pages 10877-10882Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0805205105
Keywords
Dlx; NK; lymphocyte; gene expression
Categories
Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NCI NIH HHS [P30 CA091842, P30 CA91842] Funding Source: Medline
- NIAMS NIH HHS [P30 AR048335] Funding Source: Medline
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Natural killer (NK) cells constitute a subpopulation of lymphocytes that develop from precursors in the bone marrow (BM), but the transcriptional regulation of their development and maturation is only beginning to be understood, in part due to their relatively rare abundance, especially of developmental subsets. Using a mouse model in which NK cells are arrested at an immature stage of development, and a gene expression profiling approach, we uncovered transient normal NK cell expression of a homeobox transcription factor (TF) family, called Distal-less (Dlx), which had been primarily implicated in murine CNS, craniofacial, limb, and skin development. Our studies demonstrate that Dlx1, Dlx2, and Dlx3 are transiently expressed in immature Mac-1(lo) NK cells within the BM, with Dlx3 being the predominantly expressed member. These genes are expressed in a temporally regulated pattern with overlapping waves of expression, and they display functional redundancy. Expression is extinguished in fully mature splenic NK cells, and persistent expression of Dlx genes leads to functionally immature NK cells arrested at the Mac-1(lo) stage. Whereas conventional splenic NK cells develop but are arrested at an immature stage, there appears to be a complete failure to develop CD127(+) thymic NK cells when Dlx genes are persistently expressed. We also observed that T and B cells fail to develop in the context of persistent Dlx1 expression. Thus, these studies indicate that Dlx TFs play a functional role in lymphocyte development.
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