GDNF family receptor alpha-like (GFRAL) expression is restricted to the caudal brainstem

Abstract

The TGF-{beta} cytokine, growth differentiation factor 15 (GDF15) is a critical mediator of the physiologic response to a range of cellular stresses. While circulating levels of GDF15 are normally very low, these levels increase substantially under a number of acute and chronic pathogenic states including mycotoxin exposure, infection and cancer. GDF15 controls a range of physiologic outputs including reduced appetite, gastric motility, hyperalgesia, emesis, energy expenditure and immune cell function via the GDNF family receptor alpha-like (GFRAL). While the area postrema and nucleus of the solitary tract (AP/NTS) within the caudal brainstem are the only known sites of Gfral-expressing cells, Gfral may also be expressed in other cell types. We therefore utilized single molecule in-situ hybridizations and genetic mouse models to label Gfral-expressing cells from development to adult mouse. With both approaches, we found Gfral-labelled cells in the brainstem and extremely rare Gfral-labelled cells in peripheral tissues in the mouse under normal physiological conditions. Confirming these findings, single nucleus RNA-sequencing of human tissues demonstrated nearly undetectable levels of Gfral mRNA in sites outside the AP/NTS. Our findings confirm AP/NTS neurons are the major site of Gfral expression.