Department of Physiology, School of Medicine, Jinan University, Tianhe, Guangzhou, Guangdong, China.
Cell-Gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
J Cell Physiol. 2021 Sep;236(9):6507-6519. doi: 10.1002/jcp.30325. Epub 2021 Feb 8.
The intestinal mucosa is in continuous contact with milliard of microorganisms, thus intestinal epithelial barrier is a critical component in the arsenal of defense mechanisms required to prevent infection and inflammation. Mucin 2 (MUC2), which is produced by the goblet cells, forms the skeleton of the intestinal mucus and protects the intestinal tract from self-digestion and numerous microorganisms. Dedicator of cytokinesis 4 (DOCK4) is a member of the DOCK-B subfamily of the DOCK family of guanine nucleotide exchange factors. It is reported that DOCK4 plays a critical role in the repair of the barrier function of the intestinal epithelium after chemical damage. In this study, the role of DOCK4 in the goblet cell differentiation and MUC2 production is explored. Disordered intestinal epithelium and shortage of goblet cells were observed in DOCK4 gene knockout mice. Furthermore, DOCK4 deletion contributed to the low expression of MUC2 and the goblet cell differentiation/maturation factors including growth factor independent 1 (Gfi1) and SAM pointed domain epithelial-specific transcription factor (Spdef) in mouse ileums and colons. Overexpression of DOCK4 caused a marked increase in Gfi1, Spdef, and MUC2, while siRNA knockdown of endogenous DOCK4 significantly decreased Gfi1, Spdef, and MUC2 in HT-29 cells. In addition, MUC2, DOCK4, and the goblet cell differentiation/maturation factors mRNA levels were decreased in colorectal cancer samples compared with normal colons. A significant positive correlation was found between MUC2 and DOCK4. In conclusion, DOCK4 may serve as a critical regulator of goblet cell differentiation and MUC2 production in the intestine.
肠黏膜与数以亿计的微生物持续接触，因此，肠上皮屏障是防止感染和炎症所需的防御机制的关键组成部分。黏蛋白 2（MUC2）由杯状细胞产生，它构成了肠道黏液的骨架，保护肠道免受自身消化和众多微生物的侵害。胞分裂促进因子 4（DOCK4）是 DOCK 家族的 DOCK-B 亚家族的成员，属于鸟嘌呤核苷酸交换因子。据报道，DOCK4 在化学损伤后肠道上皮屏障功能的修复中起着至关重要的作用。在本研究中，探索了 DOCK4 在杯状细胞分化和 MUC2 产生中的作用。在 DOCK4 基因敲除小鼠中观察到肠道上皮排列紊乱和杯状细胞缺失。此外，DOCK4 缺失导致小鼠回肠和结肠中 MUC2 和杯状细胞分化/成熟因子（包括生长因子独立 1（Gfi1）和 SAM 指向结构域上皮特异性转录因子（Spdef））的低表达。DOCK4 的过表达导致 Gfi1、Spdef 和 MUC2 的显著增加，而 HT-29 细胞中内源性 DOCK4 的 siRNA 敲低则显著降低了 Gfi1、Spdef 和 MUC2。此外，与正常结肠相比，结直肠癌样本中的 MUC2、DOCK4 和杯状细胞分化/成熟因子的 mRNA 水平降低。MUC2 和 DOCK4 之间存在显著的正相关。总之，DOCK4 可能是肠道中杯状细胞分化和 MUC2 产生的关键调节因子。
