GDNF promotes the survival and differentiation of minergic neurons in culture, and is able to prevent apoptosis of motor neurons induced by axotomy. The encoded protein is processed to a mature secreted form that exists as a homodimer. The mature form of the protein is a ligand for the product of the RET (rearranged during transfection) protooncogene. In addition to the transcript encoding GDNF, two additional alternative transcripts encoding distinct proteins, referred to as astrocyte-derived trophic factors, have also been described. Mutations in this gene may be associated with Hirschsprung disease.
GDNF enhances survival and morphological differentiation of minergic neurons and increases their high-affinity uptake.
GDNF is purified by proprietary chromatographic techniques.
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(a) Analysis by RP-HPLC.
(b) Analysis by SDS-PAGE.
Amino acid sequence
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Glial-Derived Neurotrophic Factor (GDNF) is a potent neurotrophic factor that plays a crucial role in the survival, development, and function of various neuronal populations. It belongs to the GDNF family of ligands (GFLs), which includes Neurturin (NRTN), Artemin (ARTN), and Persephin (PSPN). GDNF has also been known by several other names, including Hepatocyte growth factor-like protein (HGFL), Astrocyte-derived trophic factor 1 (ADTF1), Astrocyte-derived trophic factor 2 (ADTF2), and Human fibroblast-derived growth factor (HFB1-GDNF). In this article, we will review the current knowledge of GDNF and its various synonyms, including their molecular characteristics, signaling pathways, physiological functions, and therapeutic implications.
Molecular Characteristics of GDNF and Synonyms
GDNF is a protein composed of 211 amino acids with a molecular weight of approximately 23 kDa. Its primary structure consists of a signal peptide, a pro-region, and a mature protein consisting of four conserved cysteine residues that form two disulfide bonds. GDNF is highly conserved across species, with more than 90% sequence identity between human, rat, and mouse.
GDNF has been known by several synonyms throughout its discovery and characterization. One of the earliest synonyms is Astrocyte-derived trophic factor 1 (ADTF1), which was identified in 1992 by Lin et al. using a functional assay to isolate trophic factors from primary rat astrocytes. Another synonym, Astrocyte-derived trophic factor 2 (ADTF2), was identified in the same study as a separate factor with similar biological activity to ADTF1.
In 1993, GDNF was independently identified by two groups as a trophic factor for dopaminergic neurons. One group named it Human Fibroblast-Derived Growth Factor (HFB1-GDNF) based on its similarity to hepatocyte growth factor (HGF), while the other group named it Glial Cell Line-Derived Neurotrophic Factor (GDNF) based on its expression in glial cells. These two names are now used interchangeably in scientific literature.
GDNF has also been associated with other synonyms, including Atf1 and Atf2, which were identified as transcription factors that regulate the expression of GDNF in astrocytes. Atf1 and Atf2 bind to the GDNF promoter and enhance its transcriptional activity, suggesting a potential regulatory mechanism for GDNF expression.
Signaling Pathways Activated by GDNF and Synonyms
GDNF signals through a receptor complex composed of the tyrosine kinase receptor RET and a co-receptor called GDNF family receptor alpha (GFRα). GFRα exists in four isoforms, GFRα1-4, which exhibit different affinities for GDNF and its family members.
Upon binding to the receptor complex, GDNF induces RET autophosphorylation and activation of downstream signaling pathways, including the PI3K/Akt and MAPK/ERK pathways. Activation of these pathways leads to diverse cellular responses, including cell survival, differentiation, and proliferation.
GDNF has also been shown to activate other signaling pathways, including the JAK/STAT and Src family kinase pathways. These pathways are involved in regulating neuronal survival and differentiation and may contribute to GDNF's neuroprotective effects.
Physiological Functions of GDNF and Synonyms
GDNF plays critical roles in various physiological processes, particularly in the survival,