FGF-20, a Novel Neurotrophic Factor, Preferentially Expressed in the Substantia Nigra Pars Compacta of Rat Brain

Ohmachi, Shigeki; Watanabe, Yohko; Mikami, Tadahisa; Kusu, Naoki; Ibi, Tomokazu; Akaike, Akinori; Itoh, Nobuyuki

doi:10.1006/bbrc.2000.3675

Cited by 121 publications

(103 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Consistent with this finding, in situ hybridization experiments have shown that FGF20, as well as its cognate receptor (FGFR1c), is expressed in the substantia nigra pars compacta, a region of the brain where dopaminergic (DA) neurons degenerate in Parkinson's disease (42,43). Studies with cultured DA neurons show that FGF20 is capable of promoting the survival of rat DA neurons in serum-free medium or in the presence of cytotoxic concentrations of glutamate (43). FGF20 has also been shown to be able to differentiate pluripotent stem cells into DA neurons (61) and improve DA neuron survival after transplantation (54).…”

Section: Discussionmentioning

confidence: 76%

“…Single-nucleotide polymorphisms in the FGF20 gene have been associated with Parkinson's disease (64). Consistent with this finding, in situ hybridization experiments have shown that FGF20, as well as its cognate receptor (FGFR1c), is expressed in the substantia nigra pars compacta, a region of the brain where dopaminergic (DA) neurons degenerate in Parkinson's disease (42,43). Studies with cultured DA neurons show that FGF20 is capable of promoting the survival of rat DA neurons in serum-free medium or in the presence of cytotoxic concentrations of glutamate (43).…”

Section: Discussionmentioning

confidence: 79%

See 1 more Smart Citation

Homodimerization Controls the Fibroblast Growth Factor 9 Subfamily's Receptor Binding and Heparan Sulfate-Dependent Diffusion in the Extracellular Matrix

Kalinina

Byron

Makarenkova

et al. 2009

Molecular and Cellular Biology

View full text Add to dashboard Cite

Uncontrolled fibroblast growth factor (FGF) signaling can lead to human diseases, necessitating multiple layers of self-regulatory control mechanisms to keep its activity in check. Herein, we demonstrate that FGF9 and FGF20 ligands undergo a reversible homodimerization, occluding their key receptor binding sites. To test the role of dimerization in ligand autoinhibition, we introduced structure-based mutations into the dimer interfaces of FGF9 and FGF20. The mutations weakened the ability of the ligands to dimerize, effectively increasing the concentrations of monomeric ligands capable of binding and activating their cognate FGF receptor in vitro and in living cells. Interestingly, the monomeric ligands exhibit reduced heparin binding, resulting in their increased radii of heparan sulfate-dependent diffusion and biologic action, as evidenced by the wider dilation area of ex vivo lung cultures in response to implanted mutant FGF9-loaded beads. Hence, our data demonstrate that homodimerization autoregulates FGF9 and FGF20's receptor binding and concentration gradients in the extracellular matrix. Our study is the first to implicate ligand dimerization as an autoregulatory mechanism for growth factor bioactivity and sets the stage for engineering modified FGF9 subfamily ligands, with desired activity for use in both basic and translational research.Fibroblast growth factor (FGF) signaling plays pleiotropic roles throughout the life spans of mammalian organisms, ranging from germ cell maturation, mesoderm induction, body plan formation, and organogenesis during embryonic development to serum phosphate homeostasis and glucose, bile acid, lipid, and cholesterol metabolism in the adult (3,23,27,28,57,60,62). The diversity of FGF signaling is underscored by virtue of the fact that aberrant FGF signaling leads to a wide array of human diseases, including skeletal and olfactory/reproductive syndromes, phosphate wasting disorders, and cancer (16,60,67). Recent data also implicate dysregulated FGF signaling in the etiology of neurodegenerative disorders, such as major depressive disorder and Parkinson's disease (10,63,64).Based on pairwise sequence homology and phylogeny, the 18 bona fide mammalian FGFs (FGF1 to FGF10 and FGF16 to FGF23) are divided into six subfamilies (45). Five FGF subfamilies have high-to-moderate affinity for pericellular heparan sulfate (HS) glycosaminoglycans and thus diffuse locally within tissues to act in a paracrine fashion, whereas the poor affinity of the FGF19 subfamily for HS enables this subfamily to act in an endocrine manner (28, 38). All FGFs share a core homology region of about 120 amino acids, which fold into 12 antiparallel ␤ strands (␤1 to ␤12) that are arranged into three sets of four-stranded ␤ sheets (␤-trefoil fold) (39). The globular FGF core domain is flanked by highly divergent N-and C-terminal extensions, which are the principal regions responsible for the different biology of FGFs. FGFs exert their diverse actions by binding and activating FGF receptors (FGFRs) in an HS-depe...

show abstract

Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 79%

Homodimerization Controls the Fibroblast Growth Factor 9 Subfamily's Receptor Binding and Heparan Sulfate-Dependent Diffusion in the Extracellular Matrix

Kalinina

Byron

Makarenkova

et al. 2009

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…However, a truncated rat FGF-16 with 34 amino acids removed from the N terminus induces proliferation of oligodendrocytes, isolated from the rat brain, in vitro (34). It is noteworthy that FGF-16 shares 62% amino acid identity with FGF-20, whose mRNA is expressed preferentially in the brain among the adult rat major tissues and is reported to enhance the survival of midbrain dopaminergic neurons (66).…”

Section: Discussionmentioning

confidence: 99%

Specific Molecular Interactions of Oversulfated Chondroitin Sulfate E with Various Heparin-binding Growth Factors

Deepa

Umehara

Higashiyama

et al. 2002

Journal of Biological Chemistry

Self Cite

309

254

View full text Add to dashboard Cite

We previously observed that the cortical neuronal cell adhesion mediated by midkine (MK), a heparin (Hep)-binding growth factor, is specifically inhibited by oversulfated chondroitin sulfate-E (CS-E) (Ueoka, C., Kaneda, N., Okazaki, I., Nadanaka, S., Muramatsu, T., and Sugahara, K. Proteoglycans (PGs)1 that bear heparan sulfate (HS) glycosaminoglycan side chains have attracted much attention because of the demonstration of the involvement of HS in the developmental processes and specific signaling pathways (for review, see Refs. 1-3). Although the chondroitin sulfate (CS) glycosaminoglycan side chains of CS-PGs have attracted less attention until recently, accumulating evidence suggests the importance of these molecules in various biological functions (2, 4). CS-PGs are also ubiquitous components of the extracellular matrix of connective tissues and are also found at the surfaces of many cell types and in intracellular secretory granules (for review, see Refs. 5 and 6). Developmentally regulated expression of CS epitopes in the rodent fetus has been demonstrated by immunological studies (7), especially during central nervous system development (8 -10). CS is a rich component in the extracellular matrix of the brain (11). Developmentally regulated expression and tissue-specific distribution of CS variants suggest that CS chains differing in the degree and profile of sulfation perform distinct functions during development (12).Among variant forms of CS chains, oversulfated CS chains, such as CS-E and CS-D, are of special interest. The presence of E (GlcUA␤1-3GalNAc(4S,6S)) and D (GlcUA(2S)␤1-3GalNAc(6S)) units in bovine brain (13) and E18 rat brain (14) has been reported (GlcUA stands for D-glucuronic acid whereas 2S, 4S, and 6S represent 2-O-, 4-O-, and 6-O-sulfate, respectively). These units are present in appreciable proportions in chick brains, and their expression is regulated developmentally (15). Faissner et al. (16) demonstrated that the neurite outgrowth-stimulating capacity of DSD-1-PG, derived from neonatal mouse brains, is strongly reduced by the monoclonal antibody 473HD, which recognizes a CS epitope, and the interaction is inhibited by shark cartilage CS-C. We have shown that CS-D, an oversulfated CS also derived from shark cartilage, inhibits the interactions between the monoclonal antibody 473HD and DSD-1-PG and also promotes neurite outgrowth of E18 hippocampal neurons (17,18) and that the DSD-1-PG contains the D disaccharide unit, which is a rich and poor component in CS-D and CS-C, respectively. We have further observed that another oversulfated variant CS-E, derived from squid cartilage, also exhibits neurite outgrowth promoting activity, which is not inhibited by 473HD, suggesting a

show abstract

“…FGFs 1-9 range in size from ϳ150 to 260 amino acid residues and have a conserved ϳ120-amino acid residue core with ϳ30 to 70% sequence identity (Ornitz and Itoh, 2001;Itoh and Ornitz, 2004). Based on their conserved amino acid sequences, Fgfs 10 -14 and 16 -23 were isolated by conducting a homology-based polymerase chain reaction or identified by homology-based searches in nucleotide sequence databases (Yamasaki et al, 1996;Smallwood et al, 1996;Miyake et al, 1998;Hoshikawa et al, 1998;Nishimura et al, 1999Nishimura et al, , 2000Ohmachi et al, 2000;Nakatake et al, 2001;Yamashita et al, 2000). In addition, Fgf15 was identified as a downstream target of the chimeric homeodomain oncoprotein E2A-Pbx (McWhirter et al, 1997).…”

Section: Identification Of the Mouse Fgf Gene Familymentioning

confidence: 99%

Functional evolutionary history of the mouse Fgf gene family

Itoh

Ornitz

2007

Developmental Dynamics

Self Cite

352

313

View full text Add to dashboard Cite

FGF-20, a Novel Neurotrophic Factor, Preferentially Expressed in the Substantia Nigra Pars Compacta of Rat Brain

Cited by 121 publications

References 36 publications

Homodimerization Controls the Fibroblast Growth Factor 9 Subfamily's Receptor Binding and Heparan Sulfate-Dependent Diffusion in the Extracellular Matrix

Homodimerization Controls the Fibroblast Growth Factor 9 Subfamily's Receptor Binding and Heparan Sulfate-Dependent Diffusion in the Extracellular Matrix

Specific Molecular Interactions of Oversulfated Chondroitin Sulfate E with Various Heparin-binding Growth Factors

Functional evolutionary history of the mouse Fgf gene family

Contact Info

Product

Resources

About