Chd7 Is Critical for Early T-Cell Development and Thymus Organogenesis in Zebrafish.-猫眼课题宝

DOI：

10.1016/j.ajpath.2017.12.005

发表时间：

2018-04

期刊：

The American journal of pathology

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Zhi-Zhi Liu-Zhi;Zi-long Wang;Tae-Ik Choi;Wen-Ting Huang;Han-Tsing Wang;Ying-Ying Han-Ying;Lou-Yin Zhu;Hyun-Taek Kim;Jung-Hwa Choi;Jin-Soo Lee;Hyung-Goo Kim;Jian Zhao;Yue Chen;Zhuo Lu;Xiao-Li Tian;Bing-Xing Pan;Baoming Li;Cheol‐Hee Kim;Hong A. Xu

先天性缺损、心脏缺陷、先天性闭锁、生长发育迟缓、生殖器发育不全、耳畸形/耳聋（CHARGE）综合征是一种累及多个器官的先天性疾病，主要由编码染色质重塑蛋白的基因CHD 7突变引起。在CHARGE综合征中注意到免疫缺陷和T细胞减少。然而，T淋巴细胞减少症的潜在机制在很大程度上尚未探索。在此，我们观察到T细胞在两种chd 7敲除和敲除斑马鱼胚胎中均显著减少。出乎意料的是，造血干细胞和祖细胞，特别是淋巴祖细胞外周增加nonthymic地区inchd 7缺陷的胚胎，不太可能有助于T细胞减少。进一步分析表明，胸腺器官发生和归巢功能均严重受损，Chd 7可能通过调节神经嵴细胞来源的间充质细胞和咽内胚层来源的胸腺上皮细胞的发育来调节胸腺器官发生。胸腺上皮的中枢调节因子oxn 1在chd 7缺陷胚胎的咽部表达显著下调。此外，T-细胞减少inchd 7缺陷的胚胎被部分救出overexpressingfoxn 1，这表明，恢复胸腺上皮细胞可能是一个潜在的治疗策略，治疗免疫缺陷的CHARGE综合征。以上结果提示chd 7对胸腺发育至关重要，CHARGE综合征T淋巴细胞减少可能主要是胸腺器官发生缺陷所致。本研究结果对CHARGE综合征T淋巴细胞减少和免疫缺陷的诊断和治疗有一定的参考价值。

Coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness (CHARGE) syndrome is a congenital disorder affecting multiple organs and mainly caused by mutations inCHD7, a gene encoding a chromatin-remodeling protein. Immunodeficiency and reduced T cells have been noted in CHARGE syndrome. However, the mechanisms underlying T lymphopenia are largely unexplored. Herein, we observed dramatic decrease of T cells in bothchd7knockdown and knockout zebrafish embryos. Unexpectedly, hematopoietic stem and progenitor cells and, particularly, lymphoid progenitor cells were increased peripherally in nonthymic areas inchd7-deficient embryos, unlikely to contribute to the T-cell decrease. Further analysis demonstrated that both the organogenesis and homing function of the thymus were seriously impaired.Chd7might regulate thymus organogenesis through modulating the development of both neural crest cell–derived mesenchyme and pharyngeal endoderm–derived thymic epithelial cells. The expression offoxn1, a central regulator of thymic epithelium, was remarkably down-regulated in the pharyngeal region inchd7-deficient embryos. Moreover, the T-cell reduction inchd7-deficient embryos was partially rescued by overexpressingfoxn1, suggesting that restoring thymic epithelium may be a potential therapeutic strategy for treating immunodeficiency in CHARGE syndrome. Collectively, the results indicated thatchd7was critical for thymic development and T-lymphopenia in CHARGE syndrome may be mainly attributed to the defects of thymic organogenesis. The current finding may benefit the diagnosis and therapy of T lymphopenia and immunodeficiency in CHARGE syndrome.

Chd7 Is Critical for Early T-Cell Development and Thymus Organogenesis in Zebrafish.

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