INSL5 is a novel marker for human enteroendocrine cells of the large intestine and neuroendocrine tumours

Abstract

We report for the first time the distribution of human INSL5 and its cognate leucine rich G-protein coupled receptor RXFP4 in the large intestine and in neuroendocrine/carcinoid tissues. Immunoreactive INSL5 was uniquely expressed by enteroendocrine cells (EECs) located within the colonic mucosa, whereas colonocytes were immunopositive for RXFP4. INSL5+ and RXFP4+ cells were also detected in human neuroendocrine/carcinoid tissues. We employed a recently described Insl5 knockout mouse model and 2 mouse models of induced colitis to address the relevance of Insl5 in EEC development and in acute inflammation of the colon. We identified INSL5 as a specific marker for synaptophysin+ EECs in the mucosa of the normal human and mouse colon. Insl5 was not essential for the development of mouse synaptophysin+ EECs. The mouse models of chemically induced colitis (dextran sulfate sodium and dinitrobenzene-sulfonic acid) failed to show changes in the numbers of Insl5+ EECs at inflammatory sites during the acute phase of colitis. In conclusion, we showed that INSL5 is a novel marker of colorectal EECs and provide first evidence for the presence of a potentially autocrine/paracrine INSL5-RXFP4 signaling system in the normal human and mouse colon and in rare human neuroendocrine tumours.

Differentiation of Human Pluripotent Stem Cells into Colonic Organoids via Transient Activation of BMP Signaling

“…We observed higher numbers of GLP-1 and PYY cells and higher expression of preproglucagon and PYY in HCOs than in HIOs (Figure 6I–P). In addition, we found expression of the colon specific hormone INSL5 (Burnicka-Turek et al, 2012; Thanasupawat et al, 2013), only in HCOs (Figure 6Q–T). …”

“…For example, expression of the protein INSL5 is restricted to colonic EECs (Burnicka-Turek et al, 2012; Thanasupawat et al, 2013). As a functional test of colonic identity, we determined if experimental induction of the colonic EEC marker INSL5 was restricted to BMP2-treated distal organoids.…”

International Union of Basic and Clinical Pharmacology. XCV. Recent Advances in the Understanding of the Pharmacology and Biological Roles of Relaxin Family Peptide Receptors 1–4, the Receptors for Relaxin Family Peptides

“…RXFP4 mRNA is present in a variety of human tissues including brain, kidney, testis, thymus, placenta, prostate, salivary gland, thyroid, and colon (Liu et al, 2005b; Burnicka-Turek et al, 2012; Mashima et al, 2013;Thanasupawat et al, 2013). Many of these tissues also express INSL5 (Burnicka-Turek et al, 2012;Mashima et al, 2013;Thanasupawat et al, 2013), and both RXFP4 and Insl5 are pseudogenes in rats and dogs Wilkinson et al, 2005a). INSL5 was shown to be a high-affinity ligand for RXFP4 (Liu et al, 2005b), and thus the receptor-ligand coevolution, pharmacology, and similarities in expression profiles strongly indicate that RXFP4 is the endogenous receptor for INSL5.…”

Insulin-like peptide 5 is an orexigenic gastrointestinal hormone

“…It has been identified recently in colonic tissue and neuroendocrine tumors (11,12), but its function remains unclear. Although some members of the relaxin family have important roles in reproductive physiology and remodeling of connective tissue, the functions of others, including Insl5, have remained elusive (13).…”