Wnt Signaling Regulates Snai1 Expression and Cellular Localization in the Mouse Intestinal Epithelial Stem Cell Niche

Abstract

Snail genes are transcriptional repressors well known to play important roles in epithelial to mesenchymal transitions during both embryogenesis and cancer metastasis. Although they are generally regarded as markers of mesenchymal cells, Snail genes have also recently been implicated in regulating stem cell populations in both Drosophila and vertebrates. In this study we investigate Snai1, a member of the mouse Snail family, in the intestinal stem cell niche and examine the relationship between canonical Wnt signaling, a key regulatory pathway of intestinal stem cells, and expression and cellular localization of Snai1. Strong nuclear expression of Snai1 was detected in the crypt base columnar stem cells in the adult small intestine while Snai1 was mostly found in the cytoplasm of differentiated enterocytes and enteroendocrine cells. Expression and cellular localization of Snai1 in the intestinal epithelium appears to be regulated by the canonical Wnt signaling pathway as Snai1 expression was dramatically reduced after conditional deletion of β-catenin. Conversely, significant nuclear Snai1 was detected in polyps derived from Apc(min) mice and in intestinal villi after conditional mutation of Apc in AhCre, Apc(f/f) mice, indicating that upregulation of the Wnt pathway in the intestinal epithelium induces both increased expression and nuclear localization of Snai1.

Snai1 regulates cell lineage allocation and stem cell maintenance in the mouse intestinal epithelium

“…Expression levels were highest throughout embryogenesis and postnatal stages (Fig D, F, H and J); however, Snai2 expression was still detected in adult small intestine (Fig K) and adult colon (Supplementary Fig S1D) where a proximal to distal gradient of expression was apparent (Supplementary Fig S1E). Immunohistochemistry using an antibody that detects both Snai1 and Snai2 revealed expression in both the epithelium and mesenchyme (Fig C, E, G and I, and Supplementary Fig S1B and C) (Horvay et al , ). As Snai2 is not present in the epithelium, signal detected is due to expression of Snai1 .…”

miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions

“…40 Furthermore, nuclear SNAIL is expressed in the crypt base columnar stem cells in the small intestine in mice, and loss of APC resulted in increased expression of SNAIL in polyps of MIN mice. 42 miR-34 may indirectly regulate the stemness factors BMI-1 and KLF4 via repression of SNAIL and the subsequent induction of miR-200 genes, since BMI-1 and KLF4 have been characterized as direct targets of miR-200. 43 Besides the direct immediate response to minor signals and aberrant cellular reactions may be suppressed.…”

Escargot maintains stemness and suppresses differentiation in Drosophila intestinal stem cells

“…More interesting yet, mouse Snai1 is specifically expressed and required for stem cell maintenance in the crypts of the mouse intestine and expands the stem cell population when overexpressed (Horvay et al , 2011; Horvay et al, personal communication). However, few studies highlight the target genes responsible for the function of Snail family members in stem cell maintenance.…”