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

Cecilia Hes; Lu Ting Gui; Alexandre Bay; Fernando Alvarez; Pierce Katz; Tanushree Paul; Nadejda Bozadjieva-Kramer; Randy J Seeley; Ciriaco A Piccirillo; Paul V Sabatini

doi:10.1016/j.molmet.2024.102070

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

Mol Metab. 2024 Nov 26:91:102070. doi: 10.1016/j.molmet.2024.102070. Online ahead of print.

Authors

Affiliations

¹ Research Institute of the McGill University Health Centre, McGill University Health Centre, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada; Division of Experimental Medicine, Department of Medicine, McGill University, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada.
² Research Institute of the McGill University Health Centre, McGill University Health Centre, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada; Integrated Program in Neuroscience, Department of Medicine, McGill University, Room 302 Irving Ludmer Building, 1033 Pine Ave. W. Montreal, QC, H3A 1A1, Canada.
³ Research Institute of the McGill University Health Centre, McGill University Health Centre, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada.
⁴ Department of Surgery, University of Michigan, 2800 Plymouth Rd, Ann Arbor, MI, 48109, USA; Veterans Affairs Ann Arbor Healthcare System, Research Service, 2215 Fuller Rd, Ann Arbor, MI, 48105, USA.
⁵ Department of Surgery, University of Michigan, 2800 Plymouth Rd, Ann Arbor, MI, 48109, USA.
⁶ Research Institute of the McGill University Health Centre, McGill University Health Centre, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada; Department of Microbiology and Immunology, Department of Medicine, McGill University, 3775 University Street, Montreal, QC, H3A 2B4, Canada; Centre of Excellence in Translational Immunology (CETI), Research Institute of the McGill University Health Centre, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada; Program in Infectious Diseases and Immunology in Global Health, Research Institute of the McGill University Health Centre, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada.
⁷ Research Institute of the McGill University Health Centre, McGill University Health Centre, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada; Division of Experimental Medicine, Department of Medicine, McGill University, 1001 boulevard de Decarie, Montreal, QC, H4A 3J1, Canada; Integrated Program in Neuroscience, Department of Medicine, McGill University, Room 302 Irving Ludmer Building, 1033 Pine Ave. W. Montreal, QC, H3A 1A1, Canada. Electronic address: paul.sabatini@mcgill.ca.

PMID: 39608751
DOI: 10.1016/j.molmet.2024.102070

Abstract

Objective: Growth differentiation factor 15 (GDF15) acts on the receptor dimer of GDNF family receptor alpha-like (GFRAL) and Rearranged during transfection (RET). While Gfral-expressing cells are known to be present in the area postrema and nucleus of the solitary tract (AP/NTS) located in the brainstem, the presence of Gfral-expressing cells in other sites within the central nervous system and peripheral tissues is not been fully addressed. Our objective was to thoroughly investigate whether GFRAL is expressed in peripheral tissues and in brain sites different from the brainstem.

Methods: From Gfral:eGFP mice we collected tissue from 12 different tissues, including brain, and used single molecule in-situ hybridizations to identify cells within those tissues expressing Gfral. We then contrasted the results with human Gfral-expression by analyzing publicly available single-cell RNA sequencing data.

Results: In mice we found readably detectable Gfral mRNA within the AP/NTS but not within other brain sites. Within peripheral tissues, we failed to detect any Gfral-labelled cells in the vast majority of examined tissues and when present, were extremely rare. Single cell sequencing of human tissues confirmed GFRAL-expressing cells are detectable in some sites outside the AP/NTS in an extremely sparse manner. Importantly, across the utilized methodologies, smFISH, genetic Gfral reporter mice and scRNA-Seq, we failed to detect Gfral-labelled cells with all three.

Conclusions: Through highly sensitive and selective technologies we show Gfral expression is overwhelmingly restricted to the brainstem and expect that GDF15 and GFRAL-based therapies in development for cancer cachexia will specifically target AP/NTS cells.

Keywords: Area postrema; GDF15; GFRAL; Nucleus of the solitary tract.