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Background Parkinson’s disease (PD) is the second most common neurodegenerative disease and has a complex etiology. Single nucleotide polymorphisms in the 3′-untranslated region of Fibroblast growth factor 20 (FGF 20) have been reported to be associated with PD; however, the results are controversial. Although FGF20 enhances the survival of dopaminergic neurons, it may also result in PD susceptibility by altering alpha-synuclein expression. Materials and methods To identify and characterize genetic risk variants in FGF 20 in Eastern Indian PD patients, 2 SNPs of FGF 20 (rs1721100 and rs2720208) were genotyped in 336 PD cases and 313 ethnically matched controls by PCR-RFLP. Results We observed statistically significant differences in genotypic and allelic frequencies of rs1721100 between PD cases and controls but not for rs12720208. Haplotype G-C showed a significant protective effect against PD. A functional assay revealed that the risk allele C at rs1721100 has little or no effect on relative luciferase activity from a reporter construct in the presence of miR-3189-3p, whereas allele G results in significant dose-dependent reduction. Conclusion Our results suggest that FGF 20 is a susceptibility gene for PD in Eastern Indians.

The regulation of final nephron number in the kidney is poorly understood. Cessation of nephron formation occurs when the self-renewing nephron progenitor population commits to differentiation. Transcription factors within this progenitor population, such as SIX2, are assumed to control expression of genes promoting self-renewal such that homozygous Six2 deletion results in premature commitment and an early halt to kidney development. In contrast, Six2 heterozygotes were assumed to be unaffected. Using quantitative morphometry, we found a paradoxical 18% increase in ureteric branching and final nephron number in Six2 heterozygotes, despite evidence for reduced levels of SIX2 protein and transcript. This was accompanied by a clear shift in nephron progenitor identity with a distinct subset of downregulated progenitor genes such as Cited1 and Meox1 while other genes were unaffected. The net result was an increase in nephron progenitor proliferation, as assessed by elevated EdU (5-ethynyl-2′-deoxyuridine) labeling, an increase in MYC protein, and transcriptional upregulation of MYC target genes. Heterozygosity for Six2 on an Fgf20 -/- background resulted in premature differentiation of the progenitor population, confirming that progenitor regulation is compromised in Six2 heterozygotes. Overall, our studies reveal a unique dose response of nephron progenitors to the level of SIX2 protein in which the role of SIX2 in progenitor proliferation versus self-renewal is separable.

SUMMARYCell fate transitions are essential for specialization of stem cells and their niches, but the precise timing and sequence of molecular events during embryonic development are largely unknown. Here, we show that dermal condensates (DC), signaling niches for epithelial progenitors in hair placodes, are specified before niche formation and function. With 3D/4D microscopy we identify unclustered DC precursors. With population-based and single-cell transcriptomics we define a molecular time-lapse of dynamic niche signatures and the developmental trajectory as the DC lineage emerges from fibroblasts. Co-expression of downregulated fibroblast and upregulated DC genes in niche precursors reveals a transitory molecular state following a proliferation shutdown. Waves of transcription factor and signaling molecule expression then consolidate DC niche formation. Finally, ablation of epidermal Wnt signaling and placode-derived FGF20 demonstrates their requirement for DC-precursor specification. These findings uncover a progenitor-dependent niche precursor fate and the transitory molecular events controlling niche formation and function.Graphical AbstractHIGHLIGHTSPrecursors of the hair follicle niche are specified before niche cluster formationBulk/single cell RNA-seq defines early niche fate at molecular transitional stateSuccessive waves of transcription factor/signaling genes mark niche fate acquisitionNiche fate acquisition is not “pre-programmed” and requires FGF20 from progenitors

SummaryDuring fetal development, nephrons of the metanephric kidney form from a mesenchymal progenitor population that differentiates en masse before or shortly after birth. We explored intrinsic and extrinsic mechanisms controlling progenitor lifespan in a transplantation assay that allowed us to compare engraftment of old and young progenitors into the same young niche. The progenitors displayed an age-dependent decrease in proliferation and concomitant increase in niche exit rates. Single-cell transcriptome profiling revealed progressive age-dependent changes, with heterogeneity increasing in older populations. Age-dependent elevation in mTor and reduction in Fgf20 could contribute to increased exit rates. Importantly, 30% of old progenitors remained in the niche for up to 1 week post engraftment, a net gain of 50% to their lifespan, but only if surrounded by young neighbors. We provide evidence in support of a model in which intrinsic age-dependent changes affect inter-progenitor interactions that drive cessation of nephrogenesis.

Four conserved signaling pathways, including the bone morphogenetic proteins (Bmp), fibroblast growth factors (Fgf), Sonic hedgehog (Shh), and Wingless-related (Wnt) pathways, are each repeatedly used throughout tooth development. Inactivation of any of these resulted in early tooth developmental arrest in mice. The mutations identified thus far in human patients with tooth agenesis also affect these pathways. Recent studies show that these signaling pathways interact through positive and negative feedback loops to regulate not only morphogenesis of individual teeth but also tooth number, shape, and spatial pattern. Increased activity of each of the Fgf, Shh, and canonical Wnt signaling pathways revitalizes development of the physiologically arrested mouse diastemal tooth germs whereas constitutive activation of canonical Wnt signaling in the dental epithelium is able to induce supernumerary tooth formation even in the absence of Msx1 and Pax9, two transcription factors required for normal tooth development beyond the early bud stage. Bmp4 and Msx1 act in a positive feedback loop to drive sequential tooth formation whereas the Osr2 transcription factor restricts Msx1-mediated expansion of the mesenchymal odontogenic field along both the buccolingual and anteroposterior axes to pattern mouse molar teeth in a single row. Moreover, the ectodermal-specific ectodysplasin (EDA) signaling pathway controls tooth number and tooth shape through regulation of Fgf20 expression in the dental epithelium, whereas Shh suppresses Wnt signaling through a negative feedback loop to regulate spatial patterning of teeth. In this article, we attempt to integrate these exciting findings in the understanding of the molecular networks regulating tooth development and patterning.

Cell fate transitions are essential for specification of stem cells and their niches, but the precise timing and sequence of molecular events during embryonic development are largely unknown. Here, we identify, with 3D and 4D microscopy, unclustered precursors of dermal condensates (DC), signaling niches for epithelial progenitors in hair placodes. With population-based and single-cell transcriptomics, we define a molecular time-lapse from pre-DC fate specification through DC niche formation and establish the developmental trajectory as the DC lineage emerges from fibroblasts. Co-expression of downregulated fibroblast and upregulated DC genes in niche precursors reveals a transitory molecular state following a proliferation shutdown. Waves of transcription factor and signaling molecule expression then coincide with DC formation. Finally, ablation of epidermal Wnt signaling and placode-derived FGF20 demonstrates their requirement for pre-DC specification. These findings uncover a progenitor-dependent niche precursor fate and the transitory molecular events controlling niche formation and function.

DNA variations in the fibroblast growth factor 20 gene have been reported to be associated with Parkinson's disease (PD). The rs12720208, a functional SNP located in the 3'UTR region of the gene, was reported as a risk factor for PD. A number of studies, which tried to replicate the result in different populations, failed to detect any associations. In this study, we genotyped rs2720208 SNP in 520 PD patients and 520 healthy controls both from Iran. Significant differences were found in allele and genotype frequencies between patients and controls (p

In mammals, fibroblast growth factors (FGFs) are encoded by 22 genes. FGFs bind and activate alternatively spliced forms of four tyrosine kinase FGF receptors (FGFRs 1–4). The spatial and temporal expression patterns of FGFs and FGFRs and the ability of specific ligand-receptor pairs to actively signal are important factors regulating FGF activity in a variety of biological processes. FGF signaling activity is regulated by the binding specificity of ligands and receptors and is modulated by extrinsic cofactors such as heparan sulfate proteoglycans. In previous studies, we have engineered BaF3 cell lines to express the seven principal FGFRs and used these cell lines to determine the receptor binding specificity of FGFs 1–9 by using relative mitogenic activity as the readout. Here we have extended these semiquantitative studies to assess the receptor binding specificity of the remaining FGFs 10–23. This study completes the mitogenesis-based comparison of receptor specificity of the entire FGF family under standard conditions and should help in interpreting and predicting in vivo biological activity.

Fibroblast growth factor (FGF) 20 is a neurotrophic factor that exerts strong neurotrophic properties in the brain and could significantly enhance the survival of rat midbrain dopaminergic neurons. The genetic association of the FGF20 gene with Parkinson’s disease (PD) remains controversial. We used the polymerase chain reaction–restriction length polymorphism assay to assess the association of two single nucleotide polymorphisms, rs12720208 and rs1721100, within the FGF20 gene in 178 PD patients and 190 healthy controls from a Northern Han Chinese population. The results showed no significant differences in the presence of rs1721100 or rs12720208 in the FGF20 gene between PD patients and controls. This indicates the FGF20 gene might not play a major role in the genetic predisposition to PD in this population.

The pathogenic process responsible for the loss of dopaminergic neurons within the substantia nigra of patients with Parkinson disease (PD) is poorly understood. Current research supports the involvement of fibroblast growth factor (FGF20) in the survival of dopaminergic cells. FGF20 is a neurotrophic factor that is preferentially expressed within the substantia nigra of rat brain. The human homologue has been mapped to 8p21.3-8p22, which is within an area of PD linkage revealed through our published genomic screen. To test whether FGF20 influences risk of PD, we genotyped five single-nucleotide polymorphisms (SNPs) lying within the FGF20 gene, in a large family study. We analyzed our sample (644 families) through use of the pedigree disequilibrium test (PDT), the genotype PDT, the multilocus-genotype PDT, and the family-based association test to assess association between risk of PD and alleles, genotypes, multilocus genotypes, and haplotypes. We discovered a highly significant association of PD with one intronic SNP, rs1989754 (P=.0006), and two SNPs, rs1721100 (P=.02) and ss20399075 (P=.0008), located in the 3′ regulatory region in our overall sample. Furthermore, we detected a haplotype (A-G-C-C-T) that is positively associated with risk of PD (P=.0003), whereas a second haplotype (A-G-G-G-C) was found to be negatively associated with risk of PD (P=.0009). Our results strongly support FGF20 as a risk factor for PD.

In this issue of Developmental Cell, Barak et al. (2012) identify a critical role for Fgf9 and Fgf20 signaling in the nephron progenitors of the developing mammalian kidney. These Fgfs serve as survival and nephron-forming competence signals for purified Six2+ cells that represent the progenitors that normally go on to generate nephrons.