Adhesion Protein VSIG1 Is Required for the Proper Differentiation of Glandular Gastric Epithelia

Abstract

VSIG1, a cell adhesion protein of the immunoglobulin superfamily, is preferentially expressed in stomach, testis, and certain gastric, esophageal and ovarian cancers. Here, we describe the expression patterns of three alternatively spliced isoforms of mouse Vsig1 during pre- and postnatal development of stomach and potential function of Vsig1 in differentiation of gastric epithelia. We show that isoforms Vsig1A and Vsig1B, which differ in the 3′untranslated region, are expressed in the early stages of stomach development. Immunohistochemical analysis revealed that VSIG1 is restricted to the adherens junction of the glandular epithelium. The shorter transcript Vsig1C is restricted to the testis, encodes an N-terminal truncated protein and is presumably regulated by an internal promoter, which is located upstream of exon 1b. To determine whether the 5′ flanking region of exon 1a specifically targets the expression of Vsig1 to stomach epithelia, we generated and analyzed transgenic mice. The 4.8-kb fragment located upstream of exon 1a was sufficient to direct the expression of the reporter gene to the glandular epithelia of transgenic stomach. To determine the role of VSIG1 during the development of stomach epithelia, an X-linked Vsig1 was inactivated in embryonic stem cells (ESCs). Although Vsig1−/Y ESCs were only able to generate low coat color chimeric mice, no male chimeras transmitted the targeted allele to their progeny suggesting that the high contribution of Vsig1−/Y cells leads to the lethality of chimeric embryos. Analysis of chimeric stomachs revealed the differentiation of VSIG1-null cells into squamous epithelia inside the glandular region. These results suggest that VSIG1 is required for the establishment of glandular versus squamous epithelia in the stomach.

A time-resolved multi-omic atlas of the developing mouse stomach

“…The two main isoforms (NM_030181 and XM_006528630) were relatively abundant in the mouse stomach and were highly expressed at the later stages of development (Supplementary Fig. 4d ), which is consistent with a previous study 48 . If validated, these previously undetected peptides and their associated protein isoforms will identify new players in stomach development and developmental biology.…”

“…ANXA10 is a calcium- and phospholipid-binding protein expressed in the gastric mucosa 47 . VSIG1 is a cell adhesion protein required for the proper differentiation of glandular gastric epithelia 48 . CLDN18 is a gastric epithelium-associated claudin 49 .…”

A high resolution atlas of gene expression in the domestic sheep (Ovis aries)

“…Other genes exhibiting similarly large sex specific fold-changes included keratin 36 ( KRT36 ) which was expressed 6.6-fold higher in the reticulum of male relative to female sheep and VSIG1 (V-Set and immunoglobulin domain containing 1), which is required for the differentiation of glandular gastric epithelia [ 93 ]. VSIG1 showed 4-fold greater expression in the female pylorus relative to the male.…”

Characterization of V‐set and immunoglobulin domain containing 1 exerting a tumor suppressor function in gastric, lung, and esophageal cancer cells

“…In a mouse model, the cytoplasmic tail domain of VSIG1 binds to ZO‐1, an important molecule of tight junctions, through the Ser/Thr‐X‐Val/Ile motif . However, another mouse study showed that VSIG1 expressed in gastric epithelial cells was distributed along the lateral membrane of the glandular epithelia in a distribution pattern similar to adherens junctions, and that VSIG1 did not colocalize with ZO‐1 . Moreover, this motif is not present in human VSIG1.…”