Fibroblast growth factor 22 (FGF22), a target-derived presynaptic organizer that is essential for the establishment of new excitatory synapses during development and synaptic organization in adulthood, has emerged as an important endogenous factor for detour circuit formation.

(Data source: AlphaFold)

FGF22 is composed of 170 amino acids and is a secreted extracellular protein. Its main functional domain is the 23-170 segment and is mainly expressed in the skin and brain.

(Data source: Uniprot)

In 2004, a groundbreaking report in the Cell article reported that FGF22 was the target organizer of presynaptic differentiation: treatment of cultured neurons with mouse forebrain extracts led to the redistribution of synaptic vesicles in neuronal processes, forming clusters similar to presynaptic varicosities, and a major active protein was purified from the extract and identified as FGF22.

(Data source: Umemori H, et al. Cell. 2004)

FGF22 was then further identified as a key regulator of neural circuit remodeling in the injured spinal cord: FGF22 is produced by spinal relay neurons, while its main receptors FGFR1 and FGFR2 are expressed by cortical projection neurons. FGF22 deficiency or targeted deletion of FGFR1 and FGFR2 in the hindlimb motor cortex limits the formation of new synapses between corticospinal collaterals and relay neurons, delays their molecular maturation, and hinders functional recovery in a mouse model of spinal cord injury.

(Data source: Jacobi A, et al. EMBO J. 2015)

FGF22 is released from CA3 pyramidal neurons and induces the expression of insulin-like growth factor 2 (IGF2) to stabilize presynaptic terminals and organize the differentiation of excitatory nerve terminals formed on dentate granule cells (DGCs).

(Data source: Terauchi A, et al. Elife. 2016)

Based on previous research on the mechanism of FGF22 in neuronal repair and synapse formation, researchers have developed a new synaptogenesis therapy: FGF22 gene therapy, which can improve neuronal remodeling and functional recovery after spinal cord injury, and has determined the time limit for its application.

(Data source: Aljović A, et al. EMBO Mol Med. 2023)

Currently, FGF22 plays an important role in the plasticity of spinal axonal function recovery. According to reported preclinical studies, it has broad therapeutic significance for acute, subacute and chronic neurological diseases caused by synaptic loss.