Biological significance of FoxN1 gain-of-function mutations during T and B lymphopoiesis in juvenile mice.
Biological significance of FoxN1 gain-of-function mutations during T and B lymphopoiesis in juvenile mice.
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幼年小鼠 T 和 B 淋巴细胞生成过程中 FoxN1 功能获得突变的生物学意义
DOI：
10.1038/cddis.2014.432
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发表时间：
2014-10-09
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
FOXN1在皮肤和胸腺上皮细胞(TECs)中自主表达，对它们的发育至关重要。FOXN1先天突变导致毛囊和TEC发育失败，而出生后FOXN1表达不足导致胸腺萎缩，导致T淋巴细胞生成下降。尽管在FOXN1缺失的老年胸腺中上调FOXN1的表达可以恢复T淋巴细胞的生成，但其在生命早期的过度和异位表达是否有利于T淋巴细胞的生成尚不清楚。在我们新建立的rosa26-Stop Flox-FOXN1小鼠中，通过各种启动子驱动的Cre介导的早期路障FLOX的缺失可以诱导FOXN1的过度和异位表达，我们发现K14Cre介导的先天性FOXN1过度表达诱导了新生儿死亡，表现出皮肤的异常通透性和异常的护理。在幼年小鼠中，由uCreer T的渐进性渗漏所介导的Stop Flox的普遍缺失影响了胸腺和骨髓的正常，导致髓质/皮质TECs比率增加，T和B淋巴细胞生成减少。尽管K5Creer T介导的FOXN1过表达小鼠有正常的寿命，但K5Creer T在幼年的诱导激活对整个胸腺肌细胞的发育产生了不利影响，并产生了鱼鳞病样皮肤。因此，FOXN1具有时间和组织特异性活性。在生命早期，FOXN1的过度和异位表达对未成熟的TEC、T和B细胞以及皮肤上皮细胞的发育产生不利影响。
FoxN1 is cell-autonomously expressed in skin and thymic epithelial cells (TECs), essential for their development. Inborn mutation of FoxN1 results in hair follicle and TEC development failure, whereas insufficient postnatal FoxN1 expression induces thymic atrophy, resulting in declined T lymphopoiesis. Although upregulating FoxN1 expression in the aged FoxN1-declined thymus rejuvenates T lymphopoiesis, whether its over-and ectopic-expression in early life is beneficial for T lymphopoiesis is unknown. Using our newly generated Rosa26-STOP flox–FoxN1 mice, in which over-and ectopic-expression of FoxN1 can be induced by various promoter-driven Cre-mediated deletions of the roadblock STOP flox in early life, we found that K14Cre-mediated inborn FoxN1 overexpression induced neonatal lethality, exhibited abnormal permeability in the skin and abnormal nursing. Ubiquitous deletion of the STOP flox mediated by progressive uCreER T leakage in juvenile mice affected thymus and bone marrow normality, resulting in an increased ratio of medullary/cortical TECs, along with declined T and B lymphopoiesis. Although the K5CreER T-mediated FoxN1 overexpression mice had a normal lifespan, induction of K5CreER T activation in juveniles adversely influenced total thymoycte development and produced ichthyosis-like skin. Therefore, FoxN1 has temporal and tissue-specific activity. Over-and ectopic-expression of FoxN1 in early life adversely influence immature TEC, T and B cell, and skin epithelial development.
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影响因子：
9
作者：
通讯作者：
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影响因子：
4.4
作者：
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作者：
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通讯作者：
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