RAB and RHO GTPases regulate intestinal crypt cell homeostasis and enterocyte function

Abstract

Recent human and mouse genetic studies have highlighted important contributions of several small GTPases, in particular Rab8a, (1) Cdc42, (2-4) and Rab11a, (5-8) to the proper morphogenesis and function of the mature intestinal epithelia. Additional insights about the involvement of these factors in maintaining intestinal stem cell homeostasis have also been obtained. (9,10) These studies suggest a conserved vesicular and membrane trafficking program utilized by the gastrointestinal tissue to support the rapid epithelial cell turnover and the highly sophisticated physiology of mature epithelial cells.

Keywords: CDC42; Microvillus Inclusion Disease; Paneth cell; RAB11; RAB8; Wnt secretion; enterocyte; intestinal stem cell; stem cell niche.

Figure 1.

Rab8a, Rab11 and Cdc42 regulate multiple aspects of intestinal epithelial homeostasis. (A) In enterocytes, Rab8a and Rab11a mediate the transport of apical cargoes, including Glut5, NHE3 and CFTR, by recruiting Myosin 5B. The tethering of these cargo-containing vesicles to apical plasma membrane depends on Rab11a interacting with Vamp7/Stx3. Apical trafficking of brush border enzymes, including dipeptidyl peptidase IV (DPPIV), alkaline phosphatase (AlP), sucrase-isomaltase (SI) and the oligo-peptide transporter 1 (PepT1/Slc15a1), is mediated by Rab8a with little involvement of Myosin 5B and Stx3. Cdc42 navigates apical transport of Rab8a vesicles to plasma membrane. (B) In Paneth cells or other Wnt secreting cells, Rab8a facilitates Wnt3 secretion in the intestinal crypts by facilitating GPR177 transport to plasma membrane. (C) Cdc42 is cell autonomously required for the proper division and differentiation of stem cells.