Distal-less homeobox transcription factors regulate development and maturation of natural killer cells
Distal-less homeobox transcription factors regulate development and maturation of natural killer cells
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DOI：
10.1073/pnas.0805205105
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发表时间：
2008-08
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影响因子：
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通讯作者：
J. Sunwoo;Sungjin Kim;Liping Yang;Tina Naik;D. Higuchi;J. Rubenstein;W. Yokoyama
中科院分区：
文献类型：
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作者：
J. Sunwoo;Sungjin Kim;Liping Yang;Tina Naik;D. Higuchi;J. Rubenstein;W. Yokoyama
自然杀伤 (NK) 细胞是淋巴细胞的一个亚群，由骨髓 (BM) 中的前体细胞发育而来，但其发育和成熟的转录调控才刚刚开始被了解，部分原因是它们的数量相对稀少，尤其是发育亚群。使用NK细胞在发育不成熟阶段被阻滞的小鼠模型，以及基因表达谱分析方法，我们发现同源盒转录因子（TF）家族（称为Distal-less（Dlx））的瞬时正常NK细胞表达，该家族主要与小鼠中枢神经系统、颅面、四肢和皮肤发育有关。我们的研究表明，Dlx1、Dlx2 和 Dlx3 在 BM 内的未成熟 Mac-1lo NK 细胞中瞬时表达，其中 Dlx3 是主要表达的成员。这些基因以具有重叠表达波的时间调节模式表达，并且它们表现出功能冗余。完全成熟的脾 NK 细胞中的表达消失，Dlx 基因的持续表达导致功能不成熟的 NK 细胞停滞在 Mac-1lo 阶段。传统的脾 NK 细胞发育但停滞在未成熟阶段，而当 Dlx 基因持续表达时，CD127+ 胸腺 NK 细胞似乎完全无法发育。我们还观察到 T 细胞和 B 细胞在 Dlx1 持续表达的情况下无法发育。因此，这些研究表明 Dlx TF 在淋巴细胞发育中发挥功能作用。
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-1lo 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-1lo 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.