Gfra1, the glycosylphosphatidylinositol-linked GDNF (glial cell derived neurotrophic factor) receptor alpha, is a coreceptor recognizing GDNF family ligands. It plays a crucial role in the development and maintenance of the nervous system, regulating proliferation, differentiation, and migration of neuronal cells. It is also involved in the RET/GFRA1 signaling which is important for ureteric bud morphogenesis [1,5].

In GFRa1 hypomorphic mice with 70%-80% reduction in GFRa1 expression, it leads to Hirschsprung's disease and associated enterocolitis, mirroring the disease progression in children [4]. In mice, inactivation of Ash2l in the ureteric bud lineage down-regulates Gfra1 expression, causing CAKUT-like phenotypes [5]. In mouse spermatogonial stem cells, Gfra1 silencing results in their differentiation via RET tyrosine kinase inactivation [9]. In osteosarcoma cells, cisplatin treatment induces GFRA1 expression, which promotes autophagy through the SRC-AMPK signaling axis, leading to chemoresistance, and GFRA1-induced autophagy promotes tumor growth in mouse xenograft models [1,3]. In glioblastoma, the GDNF/GFRA1 signaling pathway contributes to chemo-and radioresistance, as shown by Nuclease technology knock-outs of GDNF and GFRA1 in patient-derived models [2]. In gastric cancer, tumor-associated macrophage-derived GDNF promotes liver metastasis via a GFRA1-modulated autophagy flux [7]. Biallelic loss-of-function variants of GFRA1 in humans cause lethal bilateral renal agenesis [6,8].

In conclusion, Gfra1 is essential for the development of the nervous system, spermatogenesis, and the renal system. Mouse models, especially those with Gfra1 inactivation or reduced expression, have revealed its roles in various diseases. These include Hirschsprung's disease, enterocolitis, congenital anomalies of the kidney and urinary tract, osteosarcoma chemoresistance, glioblastoma chemo-and radioresistance, gastric cancer liver metastasis, and bilateral renal agenesis. Understanding Gfra1's functions through these models provides insights into disease mechanisms and potential therapeutic targets.