Alternative splicing affecting a novel domain in the<i>C. elegans</i>EGL-15 FGF receptor confers functional specificity

Goodman, S. Jay; Branda, Catherine; Robinson, Matthew K.; Burdine, Rebecca D.; Stern, Michael

doi:10.1242/dev.00604

Cited by 58 publications

(99 citation statements)

References 32 publications

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“…Indicated are transgenic lines (#1 = otEx1262, #2 = otEx1266 for the "-5B" strains and #1 = otEx1254 for the "-5A" strain) that exclusively express the egl-15(5A) or egl-15(5B) splice variant, respectively, in an egl-15(n1456) null mutant background (26). The egl-15(n484) allele is an egl-15(5A)-specific null allele (43), egl-15(n1477) is a strong temperature-sensitive allele, and egl-17(n1377) is a null allele (27). ( (27).…”

Section: Discussionmentioning

confidence: 99%

Heparan sulfate 6-O-sulfotransferase 1 , a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism

Tornberg¹,

Sykiotis

Keefe

et al. 2011

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

160

128

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Neuronal development is the result of a multitude of neural migrations, which require extensive cell-cell communication. These processes are modulated by extracellular matrix components, such as heparan sulfate (HS) polysaccharides. HS is molecularly complex as a result of nonrandom modifications of the sugar moieties, including sulfations in specific positions. We report here mutations in HS 6-O-sulfotransferase 1 (HS6ST1) in families with idiopathic hypogonadotropic hypogonadism (IHH). IHH manifests as incomplete or absent puberty and infertility as a result of defects in gonadotropin-releasing hormone neuron development or function. IHH-associated HS6ST1 mutations display reduced activity in vitro and in vivo, suggesting that HS6ST1 and the complex modifications of extracellular sugars are critical for normal development in humans. Genetic experiments in Caenorhabditis elegans reveal that HS cell-specifically regulates neural branching in vivo in concert with other IHH-associated genes, including kal-1, the FGF receptor, and FGF. These findings are consistent with a model in which KAL1 can act as a modulatory coligand with FGF to activate the FGF receptor in an HS-dependent manner.heparan sulfotransferase | Kallmann syndrome T he coordinated assembly of the nervous system in metazoans requires the migration of the large majority of neurons from their place of origin to their final destination in the brain (1). These processes require the complex interplay of many factors, including secreted and transmembrane proteins that mediate communication between cells. The activity of such factors is greatly influenced by the extracellular environment (2). For example, heparan sulfates (HSs), a class of molecularly diverse extracellular glycosaminoglycans, have been shown to be crucial for neural development in mice (3). From work in model organisms, it has become clear that much of the function of HS during neural development is embedded within complex modification patterns of the HS sugar residues (reviewed in refs. 4 and 5). HS modification patterns serve specific and instructive functions during neural development and are believed to regulate ligand-receptor interactions (6-8). These patterns arise as the consequence of nonuniform modifications of the sugar moieties, including sulfations, deacetylations, and epimerizations that are introduced by specific HS-modifying enzymes (9) (Fig. 1A). It is unknown whether the function of HS modifications impinges on normal human development and disease susceptibility.Idiopathic hypogonadotropic hypogonadism (IHH) is a clinically and genetically heterogeneous condition that is characterized by lack of sexual maturation and infertility in the absence of other organic etiologies (10). Patients with IHH either have a normal sense of smell [normosmic IHH (nIHH)] or have an impaired sense of smell (anosmia

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Section: Discussionmentioning

confidence: 99%

Heparan sulfate 6-O-sulfotransferase 1 , a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism

Tornberg¹,

Sykiotis

Keefe

et al. 2011

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

160

128

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“…The various splice forms exhibit distinctive ligand-binding preferences. Therefore, spatial and temporal expression of the splice forms and their ligands may serve as an important control mechanism for FGF signaling (18,24). During brain development, FGF2, -3, -4, -8, and -17 and FGFR1, -2, and -3 are expressed in neural cells and adjacent inducing tissues and constitute part of an elaborate cell fate switch mechanism during the formation of the vertebrate CNS.…”

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confidence: 99%

Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys

Sun¹,

Malabunga²,

Tonra³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Leibel RL, Kussie P. Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys. Am J Physiol Endocrinol Metab 292: E964 -E976, 2007. First published November 28, 2006; doi:10.1152/ajpendo.00089.2006.-We generated three fully human monoclonal antibody antagonists against fibroblast growth factor receptor-1 (FGFR1) that potently block FGF signaling. We found that antibodies targeting the c-splice form of the receptor (FGFR1c) were anorexigenic when administered intraperitoneally three times weekly to mice, resulting in rapid, dose-dependent weight loss that plateaued (for doses Ͼ4 mg/kg) at 35-40% in 2 wk. Animals appeared healthy during treatment and regained their normal body weights and growth trajectories upon clearance of the antibodies from the bloodstream. Measurements of food consumption and energy expenditure indicated that the rapid weight loss was induced primarily by decreased energy intake and not by increased energy expenditure or cachexia and was accompanied by a greater reduction in fat than lean body mass. Hypophagia was not caused through malaise or illness, as indicated by absence of conditioned taste aversion, pica behavior, and decreased need-induced salt intake in rats. In support of a hypothalamic site of action, we found that, after intraperitoneal injections, anti-FGFR1c (IMC-A1), but not a control antibody, accumulated in the median eminence and adjacent mediobasal hypothalamus and that FGFR1c is enriched in the hypothalamus of mice. Furthermore, a single intracerebroventricular administration of 3 g of IMC-A1 via the 3rd ventricle to mice caused an ϳ36% reduction in food intake and an ϳ6% weight loss within the ensuing 24 h. Our data suggest that FGF signaling through FGFR1c may play a physiological role in hypothalamic feeding circuit and that blocking it leads to hypophagia and weight loss. energy homeostasis; hypothalamus; fibroblast growth factor receptor; food intake; obesity THE FGF-FGFR AXIS (fibroblast growth factor-fibroblast growth factor receptor) plays a central role in embryonic development, osteogenesis, tissue maintenance, and repair (24,42,46). FGF signaling is complex: at least 22 ligands are known that signal through four distinct cell surface receptors (FGFR1, -2, -3, and -4). Some FGF-knockouts (such as FGF4, -8, -9, -10, -18 and FGFR1) are embryonic lethal; others generate relatively mild phenotypes due to considerable redundancy in the signaling pathway(s) (10,24,42,46). Loss-of-function mutations in FGFR1 have been implicated in instances of hypogonadotropic hypogonadism (Kallmann syndrome), indicating a role for the receptor in human central nervous system (CNS)/hypothalamic development (45). FGF ligand-receptor binding induces receptor dimerization and autophosphorylation, leading to downstream activation of effector molecules such as mitogen-activating protein kinase (MAPK). In FGFR1, -2, and -3, alternative splicing of the exons encoding the third IgG-like domain produces either the b-or...

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“…Subsequent investigation revealed the presence of two alternative splice isoforms that differ in the retention of one of two mutually exclusive exons 3,4 . These exons (5A and 5B) are located as an atypical insertion following the N-terminal immunoglobin (IG) domain.…”

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confidence: 99%

Backbone-independent nucleic acid binding by splicing factor SUP-12 reveals key aspects of molecular recognition

et al. 2014

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Cellular differentiation is frequently accompanied by alternative splicing, enabled by the expression of tissue-specific factors which bind to pre-mRNAs and regulate exon choice. During Caenorhabditis elegans development, muscle-specific expression of the splicing factor SUP-12, together with a member of the Fox-1 family of splicing proteins, generates a functionally distinct isoform of the fibroblast growth factor receptor EGL-15. Using a combination of NMR spectroscopy and isothermal titration calorimetry, we determined the mode of nucleic acid binding by the RNA recognition motif domain of SUP-12. The calculated structures provide the first atomic details of RNA and DNA binding by the family of proteins that include SUP-12, RBM24, RBM38/RNPC1, SEB-4 and XSeb4R. This information was further used to design strategic mutations to probe the interaction with ASD-1 and to quantitatively perturb splicing in vivo.

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Alternative splicing affecting a novel domain in theC. elegansEGL-15 FGF receptor confers functional specificity

Cited by 58 publications

References 32 publications

Heparan sulfate 6-O-sulfotransferase 1 , a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism

Heparan sulfate 6-O-sulfotransferase 1 , a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism

Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys

Backbone-independent nucleic acid binding by splicing factor SUP-12 reveals key aspects of molecular recognition

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