Disease relevance of Gdnf

• Gdnf haploinsufficiency causes Hirschsprung-like intestinal obstruction and early-onset lethality in mice [1].
• Glial cell line-derived neurotrophic factor family members sensitize nociceptors in vitro and produce thermal hyperalgesia in vivo [2].
• Glial cell line-derived neurotrophic factor differentially stimulates ret mutants associated with the multiple endocrine neoplasia type 2 syndromes and Hirschsprung's disease [3].
• Glial cell line-derived neurotrophic factor (GDNF) shows potent neuroprotective as well as neurorestorative actions on the adult neurons impacted in animal models of Parkinson's disease (PD) [4].
• Exogenous glial cell line-derived neurotrophic factor (GDNF) exhibits potent survival-promoting effects on dopaminergic neurons of the nigrostriatal pathway that is implicated in Parkinson's disease and also protects neurons in forebrain ischemia of animal models [5].

Psychiatry related information on Gdnf

• Wild-type (Gdnf+/+) and Gdnf+/- mice (18 months old) were tested for locomotor activity and brain tissues were collected for measuring norepinephrine levels and uptake, as well as for morphological analysis [6].
• Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption [7].
• Glial cell-line derived neurotrophic factor (GDNF)-mediated RET tyrosine kinase signaling is implicated in the survival of several PNS and CNS neuronal populations that are important in the pathogenesis of several disorders including Parkinson's disease and drug addiction [8].
• Viral delivery of glial cell line-derived neurotrophic factor improves behavior and protects striatal neurons in a mouse model of Huntington's disease [9].

High impact information on Gdnf

• Our results indicate that Eya1 controls critical early inductive signalling events involved in ear and kidney formation and integrate Eya1 into the genetic regulatory cascade controlling kidney formation upstream of Gdnf [10].
• Gdnf expression, which is required to direct ureteric bud outgrowth via activation of the c-ret Rtk (refs 5, 6, 7, 8), is not detected in Eya1-/- metanephric mesenchyme [10].
• Here we demonstrate, by using a Xenopus embryo bioassay, that glial-cell-line-derived neurotrophic factor (GDNF), a distant member of the transforming growth factor (TGF)-beta superfamily, signals through the Ret RTK [11].
• Glial cell-line derived neurotrophic factor (GDNF) is a potent survival factor for embryonic midbrain dopaminergic, spinal motor, cranial sensory, sympathetic, and hindbrain noradrenergic neurons, and is available to these cells in vivo [12].
• Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor for dopaminergic neurons and motor neurons in culture [13].

Chemical compound and disease context of Gdnf

• Primary astrocytes were genetically modified ex vivo to express recombinant glial cell line-derived neurotrophic factor (GDNF) and subsequently were tested for their ability to provide neuroprotection to dopaminergic neurons in a 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease [14].
• Glial cell line-derived neurotrophic factor (GDNF) has been known for many years to protect and restore dopamine neurons of the substantia nigra (SN) in lesion models of parkinsonism, but much less has been known of its normal physiologic role [15].
• Protection by synergistic effects of adenovirus-mediated X-chromosome-linked inhibitor of apoptosis and glial cell line-derived neurotrophic factor gene transfer in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease [16].

Biological context of Gdnf

• This Gdnf(+/-) mutant cohort recapitulates complex features characteristic of HSCR, including dominant inheritance, incomplete penetrance, and variable severity of symptoms [1].
• The lack of one functioning Gdnf allele causes a spectrum of defects in gastrointestinal motility and predisposes the mutant mice to HSCR-like phenotypes [1].
• The experimentally induced dysmorphology associated with deregulated expression of Wnt11, Gdnf and Fgf7 genes in the early stages of organogenesis indicated a crucial role for sprouty function in coordination of epithelial-mesenchymal and stromal signalling, the sites of expression of these genes [17].
• These findings uncover an essential function for Eya 1 as a critical determination factor in acquiring metanephric fate within the intermediate mesoderm and as a key regulator of Gdnf expression during ureteric induction and branching morphogenesis [18].
• The architecture of the binding sites in the Six2 promoter, but not the binding sequence itself, is very similar to the one in the Gdnf promoter [19].

Anatomical context of Gdnf

• The reduced locomotor activity of Gdnf+/- mice was accompanied by reductions in NE transporter activity in the cerebellum and brain stem as well as decreased norepinephrine tissue levels in the LC [6].
• Glial cell line-derived neurotrophic factor promotes the development of adrenergic neurons in mouse neural crest cultures [20].
• The role of glial cell-line derived neurotrophic factor (GDNF) and neurotrophins in the development of locus coeruleus noradrenergic neurons was evaluated [21].
• Glial cell-line derived neurotrophic factor-mediated RET signaling regulates spermatogonial stem cell fate [22].
• Glial cell line-derived neurotrophic factor (GDNF) is known to support the survival of motoneurons in vitro and in vivo, as well as subpopulations of sensory neurons in vitro [23].

Associations of Gdnf with chemical compounds

• Gdnf encodes a mesenchymally produced ligand for the Ret tyrosine kinase receptor that is crucial for normal ureteric branching [24].
• Localization of nerve growth factor, neurotrophin-3, and glial cell line-derived neurotrophic factor in nestin-expressing reactive astrocytes in the caudate-putamen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated C57/Bl mice [25].
• In contrast, glial cell line-derived neurotrophic factor (GDNF)-responsive populations, which were visualized using the isolectin B-4 and thiamine monophosphatase, were severely diminished in the lumbar spinal cord, DRG, and hindlimb skin [26].
• Glial cell line-derived neurotrophic factor protects midbrain dopamine neurons from the lethal action of the weaver gene: a quantitative immunocytochemical study [27].
• Nephron endowment in glial cell line-derived neurotrophic factor (GDNF) heterozygous mice [28].

Physical interactions of Gdnf

• We have identified two Six2 binding sites in the Gdnf promoter that show similarity to the consensus DNA binding sequences of other homeobox proteins and harbor short palindromic sequences [19].
• The glial cell line-derived neurotrophic factor (GDNF) family receptor GFRalpha2 is the binding receptor for neurturin (NRTN) [29].

Regulatory relationships of Gdnf

• The transcription factor Six2 activates expression of the Gdnf gene as well as its own promoter [19].
• Exposure to GDNF (glial cell line-derived neurotrophic factor) induced de novo expression of functional receptors for Bv8 in a nonpeptidergic population of neurons [30].
• Glial cell line-derived neurotrophic factor induces histologic and functional protection of rod photoreceptors in the rd/rd mouse [31].
• In the present study, we investigated whether glial cell line-derived neurotrophic factor (GDNF) can induce activation of BMK1 through RET tyrosine kinase [32].

Other interactions of Gdnf

• Six2 expression, however, is absent, as is expression of the inducing growth factor, Gdnf [33].
• These analyses demonstrate that glial cell line-derived neurotrophic factor (GDNF) and neurturin are important for different aspects of ENS development [34].
• Wnt11 functions, in part, by maintaining normal expression levels of the gene encoding glial cell-derived neurotrophic factor (Gdnf) [24].
• Cloning strategies were used to identify a gene termed glial cell line-derived neurotrophic factor receptor-beta (GDNFR-beta) related to GDNFR-alpha [35].
• Our studies suggest that Gdf11 may be important in directing the initial outgrowth of the ureteric bud from the Wolffian duct by controlling the expression of Gdnf in the metanephric mesenchyme [36].

Analytical, diagnostic and therapeutic context of Gdnf

• Overexpression of glial cell line-derived neurotrophic factor in the CNS rescues motoneurons from programmed cell death and promotes their long-term survival following axotomy [37].
• Stem cell maintenance was enhanced by coculture with OP9 bone marrow stroma or L fibroblast cell lines, addition of glial cell line-derived neurotrophic factor, or utilization of specific culture medium [38].
• Here we demonstrate expression of glial-cell-line-derived neurotrophic factor (GDNF) family ligands and related receptors in adult mice gonads by in situ hybridization [39].
• Oral administration of royal jelly facilitates mRNA expression of glial cell line-derived neurotrophic factor and neurofilament H in the hippocampus of the adult mouse brain [40].
• Expression of glial cell line-derived neurotrophic factor (GDNF) and GDNF family receptor alpha1 in mouse taste bud cells after denervation [41].

References