Preferential neurotrophic activity of fibroblast growth factor‐20 for dopaminergic neurons through fibroblast growth factor receptor‐1c

Ohmachi, Shigeki; Mikami, Tadahisa; Konishi, Morichika; Miyake, Ayumi; Itoh, Nobuyuki

doi:10.1002/jnr.10592

Cited by 88 publications

(79 citation statements)

References 30 publications

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“…We also noted that FGF8 could support proliferation of mDA NPs, which is in agreement with previous studies (13). Interestingly, FGF20, which is implicated in mDA survival (19), did not support proliferation of mDA NPs, showing specificity among FGF family members in supporting mDA NP proliferation.…”

Section: Discussionsupporting

confidence: 92%

“…We next investigated the self-renewability (or expandability) of Otx2 + Corin + cells in response to various signaling molecules. We tested those factors implicated in the regulation of mDA NPs (e.g., Shh, FGF8, Wnt1, and Wnt5a) (2,(10)(11)(12)(13)(14) or the proliferation of general NPs (e.g., bFGF, EGF, Dll4, and Jag1) (15-18) as well as FGF20, which was implicated in mDA survival (19). Each factor was added for a week to mitogen-free media (ND media), which by itself does not support the proliferation of purified cells.…”

Section: Results Mda Nps Can Be Identified By Coexpression Of Otx2 Anmentioning

confidence: 99%

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ES cell-derived renewable and functional midbrain dopaminergic progenitors

Chung

Moon

Leung

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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During early development, midbrain dopaminergic (mDA) neuronal progenitors (NPs) arise from the ventral mesencephalic area by the combined actions of secreted factors and their downstream transcription factors. These mDA NPs proliferate, migrate to their final destinations, and develop into mature mDA neurons in the substantia nigra and the ventral tegmental area. Here, we show that such authentic mDA NPs can be efficiently isolated from differentiated ES cells (ESCs) using a FACS method combining two markers, Otx2 and Corin. Purified Otx2 + Corin + cells coexpressed other mDA NP markers, including FoxA2, Lmx1b, and Glast. Using optimized culture conditions, these mDA NPs continuously proliferated up to 4 wk with almost 1,000-fold expansion without significant changes in their phenotype. Furthermore, upon differentiation, Otx2 + Corin + cells efficiently generated mDA neurons, as evidenced by coexpression of mDA neuronal markers (e.g., TH, Pitx3, Nurr1, and Lmx1b) and physiological functions (e.g., efficient DA secretion and uptake). Notably, these mDA NPs differentiated into a relatively homogenous DA population with few serotonergic neurons. When transplanted into PD model animals, aphakia mice, and 6-OHDA-lesioned rats, mDA NPs differentiated into mDA neurons in vivo and generated well-integrated DA grafts, resulting in significant improvement in motor dysfunctions without tumor formation. Furthermore, grafted Otx2 + Corin + cells exhibited significant migratory function in the host striatum, reaching >3.3 mm length in the entire striatum. We propose that functional and expandable mDA NPs can be efficiently isolated by this unique strategy and will serve as useful tools in regenerative medicine, bioassay, and drug screening.neural precursors | dopaminergic neurons | transplantation

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Section: Discussionsupporting

confidence: 92%

Section: Results Mda Nps Can Be Identified By Coexpression Of Otx2 Anmentioning

confidence: 99%

ES cell-derived renewable and functional midbrain dopaminergic progenitors

Chung

Moon

Leung

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…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: 74%

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

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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...

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“…FGF-20 was originally cloned from an adult rat brain cDNA library and was shown to be preferentially expressed in adult SNpc neurons (Ohmachi et al, 2000). FGF-20 can activate its receptor, FGFR1c [a splice variant of FGF receptor 1 (FGFR1)], to initiate signaling in midbrain cultured cells (Ohmachi et al, 2003). Human FGF-20 has also been cloned, and its gene has been localized to the chromosome 8p22.3-p23 region (Kirikoshi et al, 2000).…”

Section: Introductionmentioning

confidence: 99%