Biology of RET receptor and its ligands: focus on the nervous system

The receptor tyrosine kinase RET (Rearranged during Transfection) is critical for many physiological processes, particularly in the development and function of the nervous system, male reproductive and renal systems. RET signaling is activated physiologically by glial cell line-derived neurotrophic factor family (GDNF) ligands or growth differentiation factor 15 (GDF15) via GDNF family receptor α (GFRα) or GDNF family receptor α-like (GFRAL) co-receptors respectively, regulating a variety of cellular responses including cell survival, migration, differentiation, proliferation, and metabolism. RET is essential for neuronal development, maintenance, and axon guidance in the nervous system. RET signaling is critical for kidney and spermatogonia development and the enteric nervous system (ENS) development and maintenance. Inactivating mutations in the receptor is the primary cause of Hirschsprung disease, a rare intestinal motility disorder characterized by aganglionic megacolon. This review covers the molecular mechanism of RET signaling, its role in the early stages of the nervous system and kidney development during early embryogenesis, and different diseases. It highlights the importance of RET receptors as therapeutic targets.