DOCK4 stimulates MUC2 production through its effect on goblet cell differentiation

• Published in: Journal of cellular physiology 2021-09, Vol.236 (9), p.6507-6519
• Main Authors: Qin, Tingfeng, Yang, Jie, Huang, Dayin, Zhang, Zhijun, Huang, Yanling, Chen, Hui, Xu, Geyang
• Format: Article
• Language: English
• Subjects: Animals; Cell differentiation; Cell Differentiation - genetics; Chemical damage; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Critical components; Cytokinesis; Differentiation (biology); DOCK4; Epithelium; Gene deletion; Gene Expression Regulation; goblet cell differentiation; Goblet cells; Goblet Cells - cytology; Goblet Cells - metabolism; Growth factors; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Guanine; Guanine nucleotide exchange factor; HT29 Cells; Humans; Inflammation; intestinal barrier; Intestinal Mucosa - pathology; Intestine; Maturation; Mice; Mice, Knockout; Microorganisms; Models, Biological; MUC2; Mucin; Mucin-2 - biosynthesis; Mucosa; Mucus; Nucleotides; siRNA
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.30325

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. Disordered intestinal epithelium and shortage of goblet cells were observed in DOCK4 gene knockout mice. Muc2, Gfi1, and Spdef were decreased in DOCK4 null mouse ileum compared with controls. Overexpression of DOCK4 increased GFI1, SPEDF, and MUC2 expression in HT‐29 cells. siRNA knockdown of endogenous DOCK4 decreased GFI1, SPEDF, and MUC2 in HT‐29 cells. Downregulation of SPDEF, MUC2, and DOCK4 was identified in CRC compared with normal colons and a positive correlation was found between MUC2 and DOCK4.