InteractiveFly: GeneBrief

Mayo: Biological Overview | References

Adhesion G-protein-coupled receptors (aGPCRs) form a large family of cell surface molecules with versatile tasks in organ development. Many aGPCRs still await their functional and pharmacological deorphanization. This study characterized the orphan aGPCR mayo^KO (identity crisis) mutants can be restored by pharmacological inhibition of potassium channels. Intriguingly, hyperkalemia and tachycardia are caused non-cell autonomously through mayo-dependent control of enterocyte proliferation in the larval midgut, which is the primary function of this aGPCR. These findings characterize the ancestral aGPCR Mayo as a homeostatic regulator of gut development (Contreras, 2024).

The gastrointestinal (GI) tracts in Drosophila and vertebrate species share features of anatomical and functional compartmentalization. The foregut (equivalent to the mammalian esophagus) passes ingested food to the crop (stomach), the anterior midgut (small intestine) controls nutrient, ion, and water absorption, and, finally, the hindgut (large intestine) is involved in electrolyte reabsorption from the Malpighian tubules (equivalent to the kidney in mammals). Instead of the crypt-villus structure found in mammals, the Drosophila midgut consists of a monolayer populated by different cell types. Before pupation, the larval midgut is composed of enterocytes (ECs), which derive from principal midgut epithelial cells (PMECs), interstitial cell precursors (ICPs), and adult midgut precursors (AMPs), which generate and are enveloped by peripheral cells (PCs). AMPs are also thought to give rise to enteroendocrine cells (EEs). The larval AMPs, ensheathed by PCs, constitute a stem cell niche for transient pupal midgut development until metamorphosis and also the generation of the adult midgut. Dysregulation of midgut cell proliferation can lead to malabsorption of nutrients and defective ion homeostasis (Contreras, 2024).

Adhesion G-protein-coupled receptors (aGPCRs) are a large group of surface sensors with various functions in tissue development. For example, aGPCRs exert control of vital aspects of embryogenesis and cardiogenesis, as well as nervous and immune systems development. Genetic dysfunctions of aGPCRs are associated with various human pathologies such as multiple cancers, neurodevelopmental disord ol over asymmetric mitotic activity of PMECs to yield a fixed EC pool. As previously shown, the aGPCR Cirl exerts a similar effect to adjust the number of neuroblasts in the larval brain of Drosophila melanogaster, and its homolog LAT-1 controls mitotic spindle positioning and division planes of early blastomeres in C. elegans (Contreras, 2024).

Also, adult guts of mayo^KO flies were elongated. A similar phenotype was reported after overexpression of CD97/ADGRE5 in mouse intestinal epithelial cells, which caused a mega-intestine through cylindrical growth, showing that aGPCRs partake in GI development in other species too (Contreras, 2024).

In order to clarify which cell type relies on mayo function, this study harnessed the observation that mayo^KO larvae display a marked non-cell-autonomous tachycardia likely caused by a mild hyperkalemia. This is in line with the role of K+ currents in the repolarization of the Drosophila heart, while Na+ does not affect the heart frequency in Drosophila. Further, cardiac action potentials in invertebrates are carried by K+ and Ca2+ fluxes, and K+ channel mutations can cause cardiac arrhythmias, confirming the involvement of K+ channels in the regulation of the cardiac pacemaker (Contreras, 2024).

This study utilized the tachycardia in mayo^KO larvae in a screen to test which cells require mayo autonomously to maintain physiological K+ hemolymph levels. Only removal of mayo from PCs and ECs resulted in tachycardiac frequencies, showing that mayo is not only expressed but also required in those cells for the maintenance of a normal cardiac heart frequency (Contreras, 2024).

The first characterization of the aGPCR mayo in Drosophila has provided insights into its role in the larval midgut as a potential mitotic suppressor at the PMEC-EC transition. Future studies will need to clarify which molecular function mayo serves in ECs and PCs and how it does so. To this end, it is necessary to determine Mayo ligands and intracellular signaling conduits to reconstruct the receptor's signaling pathway. In particular, how Mayo is integrated into the mechanisms of EC proliferation will be of prime interest. This will shed light on how removal of mayo causes an increase in EC number and whether its mode of action is comparable to effects of other aGPCRs on mitotic activity, cell polarity, division, and fate determination (Contreras, 2024).

In conjunction with the proliferative effect of mayo removal on ECs it is concluded that this cell type likely affects K+ uptake into the hemolymph either directly through ion channels or transporters/exchange proteins, or indirectly by controlling the abundance of enteric cell types that express them. Thus, future work needs to address whether the extracellular potassium concentration simply scales with the EC number, or whether mayo impacts potassium flux phenomena in ECs as well (Contreras, 2024).

Search PubMed for articles about Drosophila Mayo

Contreras, F. V., Auger, G. M., Muller, L., Richter, V., Huetteroth, W., Seufert, F., Hildebrand, P. W., Scholz, N., Thum, A. S., Ljaschenko, D., Blanco-Redondo, B., Langenhan, T. (2024). The adhesion G-protein-coupled receptor mayo/CG11318 controls midgut development in Drosophila. Cell Rep, 43(1):113640 PubMed ID: 38180839

date revised: 5 August 2024

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