Abstract
Guanylin (GN) and uroguanylin (UGN), through activation of guanylyl cyclase C (GCC), serve to control intestinal fluid homeostasis. Both peptides are produced in the intestinal epithelium, but their cellular origin has not been fully charted. Using quantitative PCR and an improved in situ hybridization technique (RNAscope), we have assessed the expression of GN (Guca2a), UGN (Guca2b), and GCC (Gucy2c) in mouse intestine. In the crypts of Lieberkühn, expression of Guca2a and Guca2b was restricted to cells of secretory lineage, at the crypt’s base, and to a region above, previously identified as a common origin of cellular differentiation. In this compartment, comparatively uniform levels of Guca2a and Guca2b expression were observed throughout the length of the gut. In contrast, Guca2a and Guca2b expression in the villus–surface region was more variable, and reflected the distinct, but overlapping expression pattern observed previously. Accordingly, in jejunum and ileum, Guca2a and Guca2b were abundantly expressed by enterocytes, whereas in colon only Guca2a transcript was found in the surface region. In duodenum, only low levels of Guca2b transcript were observed in columnar cells, and Guca2a expression was restricted entirely to cells of the secretory lineage. Gucy2c was shown to be expressed relatively uniformly along the rostrocaudal and crypt–villus axes and was also found in the duodenal glands. Our study reveals novel aspects of the cellular localization of the GCC signaling axis that, apart from its role in the regulation of fluid balance, link it to pH regulation, cell cycle control, and host defense.Electronic supplementary materialThe online version of this article (doi:10.1007/s00418-016-1453-4) contains supplementary material, which is available to authorized users.
Highlights
Signal transduction through the receptor–enzyme guanylyl cyclase C (GCC) serves to control intestinal fluid balance
It has become apparent that local bicarbonate production is crucial for the proper expansion of the mucins produced by goblet cells, and, the physiochemical properties of the mucus layer covering the epithelium along the entire tract (Garcia et al 2009; Gustafsson et al 2012)
The distribution pattern that emerged for these transcripts closely matched the expression profile assessed by Quantitative polymerase chain reaction (qPCR) analysis, i.e., the gradual increase of Guca2a and Guca2b expression from duodenum to the distal small intestine, the high expression of Guca2a, but low expression of Guca2b, in colon, and the comparatively low expression of Gucy2c (Fig. 2)
Summary
Signal transduction through the receptor–enzyme guanylyl cyclase C (GCC) serves to control intestinal fluid balance. Activation of the luminal, extracellular receptor domain by one of two locally produced peptides, guanylin (GN) and uroguanylin (UGN), leads to a surge in cellular cGMP levels, which prompts osmotic water transport to the intestinal lumen by protein kinase-mediated stimulation of anion secretion through the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel and inhibition of sodium absorption through the sodium-proton exchanger type 3 (NHE3) (Vaandrager 2002) This pivotal role of GCC signaling in intestinal fluid balance is most poignantly illustrated by gain- and loss-of-function mutations in GUCY2C (encoding GCC), which have been shown to cause secretory diarrhea and intestinal obstruction, Histochem Cell Biol (2016) 146:445–455 respectively (Romi et al 2012; Fiskerstrand et al 2012; Muller et al 2015). Connected to its effect on mucin unfolding and fluid transport, loss of GCC signaling was shown to impair epithelial barrier function and innate host responses to bacterial pathogens (Mann et al 2013; Han et al 2011)
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