Glial cell line-derived neurotrophic factor signaling pathway (GDNF signaling pathway)

The Glial cell line-derived neurotrophic factor (GDNF) signaling pathway is a vital biological system responsible for the development, survival, and maintenance of various neuronal populations, most notably midbrain dopaminergic neurons and spinal motor neurons [Airaksinen & Saarma, 2002]. Signaling is initiated by the binding of the GDNF ligand to its high-affinity co-receptor, GFRα1, which subsequently facilitates the dimerization and autophosphorylation of the RET receptor tyrosine kinase [Sariola & Saarma, 2003]. This molecular assembly activates downstream intracellular pathways such as PI3K/Akt, MAPK/ERK, and PLCγ, which are essential for cell proliferation, differentiation, and anti-apoptotic responses [Airaksinen & Saarma, 2002]. In the context of neurodegenerative disorders like Parkinson's disease, the pathway is targeted for its neuroprotective potential, with clinical trials exploring the delivery of recombinant GDNF or gene therapies to the striatum [Allen et al., 2013]. Conversely, gain-of-function mutations or chromosomal rearrangements in the RET gene lead to constitutive pathway activation, driving malignancies like medullary thyroid carcinoma and certain lung adenocarcinomas [Subbiah et al., 2020]. Consequently, the pathway is a dual-natured therapeutic target, where agonists are sought for neurorestoration and potent kinase inhibitors like selpercatinib are utilized for oncology [Subbiah et al., 2020; Mulligan, 2014].

Other names

GDNF-GFRα1-RET axisGDNF family ligand signalingGFL signaling pathwayGlial cell line-derived neurotrophic factor receptor signaling

The pathway is modulated either by ligand-mimetic activation of the RET receptor tyrosine kinase to promote neuronal survival and restoration, or by small-molecule inhibition of the RET kinase domain to block oncogenic signaling driven by mutations or fusions [Airaksinen & Saarma, 2002; Subbiah et al., 2020].