Distinct roles for fibroblast growth factor signaling in cerebellar development and medulloblastoma

Emmenegger, Brian A.; Hwang, Eui-Hyoung; Moore, Colin; Markant, Shirley L.; Brun, Sonja N.; Dutton, John; Read, Tracy Ann; Fogarty, Marie P.; Singh, Alok R.; Durden, Donald L.; Yang, Chao; McKeehan, Wallace L.; Wechsler‐Reya, Robert J.

doi:10.1038/onc.2012.440

Cited by 30 publications

(37 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, phosphorylation of FRS2 by FGFRs activates not only the PI3K/ AKT pathway (through Grb2/Gab1 binding; Ong et al, 2001), but also the MAPK/ERK pathway (through Grb2/Shp2 binding; Hadari et al, 1998). Indeed, deletion of FGFR1 and/or FGFR2 leads to decreases in phospho-MAPK/ERK and phospho-AKT levels (Emmenegger et al, 2013;Zhao et al, 2008;Cai et al, 2013;Hoch and Soriano, 2006;Loilome et al, 2009;Kondo et al, 2007), and overexpression of FGFR2b or FGFR1 increases both phospho-AKT and phospho-ERK levels (Cha et al, 2008;Freeman et al, 2003;Acevedo et al, 2007). It is known that crosstalk can occur between the PI3K/AKT and MAPK/ERK pathways (Moelling et al, 2002), thus, possibly, the MAPK/ERK pathway is being triggered congruently.…”

Section: Discussionmentioning

confidence: 99%

Distinct sets of FGF receptors sculpt excitatory and inhibitory synaptogenesis

et al. 2015

View full text Add to dashboard Cite

Neurons in the brain must establish a balanced network of excitatory and inhibitory synapses during development for the brain to function properly. An imbalance between these synapses underlies various neurological and psychiatric disorders. The formation of excitatory and inhibitory synapses requires precise molecular control. In the hippocampus, the structure crucial for learning and memory, fibroblast growth factor 22 (FGF22) and FGF7 specifically promote excitatory or inhibitory synapse formation, respectively. Knockout of either Fgf gene leads to excitatory-inhibitory imbalance in the mouse hippocampus and manifests in an altered susceptibility to epileptic seizures, underscoring the importance of FGF-dependent synapse formation. However, the receptors and signaling mechanisms by which FGF22 and FGF7 induce excitatory and inhibitory synapse differentiation are unknown. Here, we show that distinct sets of overlapping FGF receptors (FGFRs), FGFR2b and FGFR1b, mediate excitatory or inhibitory presynaptic differentiation in response to FGF22 and FGF7. Excitatory presynaptic differentiation is impaired in Fgfr2b and Fgfr1b mutant mice; however, inhibitory presynaptic defects are only found in Fgfr2b mutants. FGFR2b and FGFR1b are required for an excitatory presynaptic response to FGF22, whereas only FGFR2b is required for an inhibitory presynaptic response to FGF7. We further find that FGFRs are required in the presynaptic neuron to respond to FGF22, and that FRS2 and PI3K, but not PLCγ, mediate FGF22-dependent presynaptic differentiation. Our results reveal the specific receptors and signaling pathways that mediate FGF-dependent presynaptic differentiation, and thereby provide a mechanistic understanding of precise excitatory and inhibitory synapse formation in the mammalian brain.

show abstract

Section: Discussionmentioning

confidence: 99%

Distinct sets of FGF receptors sculpt excitatory and inhibitory synaptogenesis

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Recent studies have shown that Bcl6 overexpression (Tiberi et al, 2014) or direct FGF injection reduces proliferation of medulloblastoma cells in which Shh is hyperactivated (Emmenegger et al, 2013), supporting the idea that enhancing differentiation effectively prevents medulloblastoma progression in vivo.…”

Section: Pals1 Loss Forces Cell Cycle Exit Despite Hyperactive Shh Simentioning

confidence: 76%

Apical complex protein Pals1 is required to maintain cerebellar progenitor cells in a proliferative state

et al. 2015

View full text Add to dashboard Cite

Through their biased localization and function within the cell, polarity complex proteins are necessary to establish the cellular asymmetry required for tissue organization. Well-characterized germinal zones, mitogenic signals and cell types make the cerebellum an excellent model for addressing the crucial function of polarity complex proteins in the generation and organization of neural tissues. Deletion of the apical polarity complex protein Pals1 in the developing cerebellum results in a remarkably undersized cerebellum with disrupted layers in poorly formed folia and strikingly reduced granule cell production. We demonstrate that Pals1 is not only essential for cerebellum organogenesis, but also for preventing premature differentiation and thus maintaining progenitor pools in cerebellar germinal zones, including cerebellar granule neuron precursors in the external granule layer. In the Pals1 mouse mutants, the expression of genes that regulate the cell cycle was diminished, correlating with the loss of the proliferating cell population of germinal zones. Furthermore, enhanced Shh signaling through activated Smo cannot overcome impaired cerebellar cell generation, arguing for an epistatic role of Pals1 in proliferation capacity. Our study identifies Pals1 as a novel intrinsic factor that regulates the generation of cerebellar cells and Pals1 deficiency as a potential inhibitor of overactive mitogenic signaling.

show abstract

“…During normal cerebellar GCP development, growth factors (GF), such as bFGF, antagonize Shh-pathway activity and promote differentiation (29, 30). When SMB cells were exposed to growth factors that are common components of stem cell media (bFGF and EGF; 20 ng/mL) both PI3K-AKT and RAS-RAF-MAPK pathways were activated, Shh signaling was suppressed, and SMB cells became resistant to LDE225 (Fig.…”

Section: Resultsmentioning

confidence: 99%

RAS/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway–Dependent Tumors

et al. 2015

View full text Add to dashboard Cite

Aberrant Shh signaling promotes tumor growth in diverse cancers. The importance of Shh signaling is particularly evident in medulloblastoma and basal cell carcinoma (BCC), where inhibitors targeting the Shh pathway component Smoothened (Smo) show great therapeutic promise. However, the emergence of drug resistance limits long-term efficacy and the mechanisms of resistance remain poorly understood. Using new medulloblastoma models, we identify two distinct paradigms of resistance to Smo inhibition. Sufu mutations lead to maintenance of the Shh pathway in the presence of Smo inhibitors. Alternatively activation of the RAS/MAPK pathway circumvents Shh pathway-dependency, drives tumor growth and enhances metastatic behavior. Strikingly, in BCC patients treated with Smo inhibitor, squamous cell cancers with RAS/MAPK activation emerged from the antecedent BCC tumors. Together these findings reveal a critical role of RAS/MAPK pathway in drug resistance and tumor evolution of Shh pathway-dependent tumors.

show abstract

Distinct roles for fibroblast growth factor signaling in cerebellar development and medulloblastoma

Cited by 30 publications

References 65 publications

Distinct sets of FGF receptors sculpt excitatory and inhibitory synaptogenesis

Distinct sets of FGF receptors sculpt excitatory and inhibitory synaptogenesis

Apical complex protein Pals1 is required to maintain cerebellar progenitor cells in a proliferative state

RAS/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway–Dependent Tumors

Contact Info

Product

Resources

About