A Gfrα3 Conditional Knockout Mouse Reveals a Requirement for GFRα3 / RET Signaling in Cholecystokinin‐Positive Enteroendocrine Cells

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ABSTRACT The receptor tyrosine kinase RET regulates the development of multiple neuronal populations through GFRα co‐receptors and their cognate ligands. Recent work has shown that RET is also required for enteroendocrine cell (EEC) function; however, the specific GFRα receptor operating in EECs has remained unclear. Here, we identify GFRα3 as the predominant GFRα receptor expressed in EECs. To determine its cell‐autonomous role, we generated a Gfrα3 conditional allele and inactivated the Gfrα3 gene specifically in the intestinal epithelium. These Gfrα3 IEcKO mice exhibited a selective reduction in the number of CCK + EECs among multiple EEC subtypes. A comparative decrease in CCK + EECs in Ret IEcKO mice suggests that RET/GFRα3 signaling is required for the development and/or maintenance of this EEC lineage. Although CCK + EECs can indirectly influence glucose metabolism, Gfrα3 IEcKO mice showed no significant change in glucose tolerance under high‐fat diet (HFD) conditions. In contrast, they exhibited modest lipid malabsorption on HFD. Together, these findings demonstrate that GFRα3 is implicated in the structure and function of CCK EECs and highlight the utility of the Gfrα3 conditional allele for dissecting the biology of GFRα3‐expressing cells.

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