Developmental Regulation of Gonadotropin-Releasing Hormone Neurons by Fibroblast Growth Factor Signaling

Gill, John C.; Moenter, Suzanne M.; Tsai, Pei‐San

doi:10.1210/en.2004-0214

Cited by 76 publications

(68 citation statements)

References 57 publications

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“…Anosmin-1 and FGFR1 are known to be involved in GnRH neuron migration and neurite outgrowth (25,34,44,45). We now report that anosmin-1 can function as a chemoattractant inducing migration of immortalized FNC-B4-hTERT cells via an FGFR1-and HS-dependent mechanism (Fig.…”

Section: Discussionmentioning

confidence: 99%

Novel Mechanisms of Fibroblast Growth Factor Receptor 1 Regulation by Extracellular Matrix Protein Anosmin-1

Guimond

Travers

et al. 2009

Journal of Biological Chemistry

101

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Activation of fibroblast growth factor (FGF) signaling is initiated by a multiprotein complex formation between FGF, FGF receptor (FGFR), and heparan sulfate proteoglycan on the cell membrane. Cross-talk with other factors could affect this complex assembly and modulate the biological response of cells to FGF. We have previously demonstrated that anosmin-1, a glycosylated extracellular matrix protein, interacts with the FGFR1 signaling complex and enhances its activity in an IIIc isoformspecific and HS-dependent manner. The molecular mechanism of anosmin-1 action on FGFR1 signaling, however, remains unknown. Here, we show that anosmin-1 directly binds to FGFR1 with high affinity. This interaction involves domains in the N terminus of anosmin-1 (cysteine-rich region, whey acidic protein-like domain and the first fibronectin type III domain) and the D2-D3 extracellular domains of FGFR1. In contrast, anosmin-1 binds to FGFR2IIIc with much lower affinity and displays negligible binding to FGFR3IIIc. We also show that FGFR1-bound anosmin-1, although capable of binding to FGF2 alone, cannot bind to a FGF2⅐heparin complex, thus preventing FGFR1⅐FGF2⅐heparin complex formation. By contrast, heparinbound anosmin-1 binds to pre-formed FGF2⅐FGFR1 complex, generating an anosmin-1⅐FGFR1⅐FGF2⅐heparin complex. Furthermore, a functional interaction between anosmin-1 and the FGFR1 signaling complex is demonstrated by immunofluorescence co-localization and Transwell migration assays where anosmin-1 was shown to induce opposing effects during chemotaxis of human neuronal cells. Our study provides molecular and cellular evidence for a modulatory action of anosmin-1 on FGFR1 signaling, whereby binding of anosmin-1 to FGFR1 and heparin can play a dual role in assembly and activity of the ternary FGFR1⅐FGF2⅐heparin complex. FGF5 signaling plays an important role in a wide range of fundamental biological responses (1-3). Both FGF and FGFR bind to heparan sulfate (HS) and heparin, a highly sulfated type of HS produced in connective tissue mast cells. Heparan sulfate proteoglycans (HSPG) are the cell surface co-receptors essential for the formation of functional FGF⅐FGFR signaling complex (4, 5). There are four structurally related FGFRs (FGFR1-4), which consist of an extracellular ligand-binding region containing three immunoglobulin (Ig)-like domains (D1-D3), a single transmembrane domain, and a cytoplasmic domain with protein-tyrosine kinase catalytic activity. The 22 members of the FGF family bind to the interface formed by the D2/D3 domains and the linker between these domains (6, 7), whereas a conserved positively charged region in D2 serves as the HS binding site (8). An unusual stretch of seven to eight acidic residues designated as the "acid box" is present in the linker connecting D1 and D2. Alternative splicing events occur to generate various isoforms, including a truncated receptor lacking D1 and the D1-D2 linker or a full-length receptor that differs in the second half of D3, designated as IIIb and IIIc isoforms (5). Two cry...

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Section: Discussionmentioning

confidence: 99%

Novel Mechanisms of Fibroblast Growth Factor Receptor 1 Regulation by Extracellular Matrix Protein Anosmin-1

Guimond

Travers

et al. 2009

Journal of Biological Chemistry

101

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“…In subjects with nIHH, FGFR1 mutations may lead to an isolated defect in GnRH neuron migration. Indeed, disruptive GnRH neuronal migration in the presence of normal olfactory bulbs and sulci has been demonstrated in the knockout mouse model for another gene, Ebf2 (28). Alternatively, FGFR1 mutations could cause a defect in differentiation or survival of GnRH neurons within the hypothalamus.…”

Section: Discussionmentioning

confidence: 99%

Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism

Pitteloud

Acierno

Meysing

et al. 2006

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

217

183

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Mutations in KAL1 and FGFR1 cause Kallmann syndrome (KS), whereas mutations in the GNRHR and GPR54 genes cause idiopathic hypogonadotropic hypogonadism with normal olfaction (nIHH). Mixed pedigrees containing both KS and nIHH have also been described; however, the genetic cause of these rare cases is unknown. We examined the FGFR1 gene in seven nIHH subjects who either belonged to a mixed pedigree (n ‫؍‬ 5) or who had associated midline defects (n ‫؍‬ 2). Heterozygous FGFR1 mutations were found in three of seven unrelated nIHH probands with normal MRI of the olfactory system: (i) G237S in an nIHH female and a KS brother; (ii) (P722H and N724K) in an nIHH male missing two teeth and his mother with isolated hyposmia; and (iii) Q680X in a nIHH male with cleft lip͞palate and missing teeth, his brother with nIHH, and his father with delayed puberty. We show that these mutations lead to receptor loss-of-function. The Q680X leads to an inactive FGFR1, which lacks a major portion of the tyrosine kinase domain (TKD). The G237S mutation inhibits proper folding of D2 of the FGFR1 and likely leads to the loss of cell-surface expression of FGFR1. In contrast, the (P722H and N724K) double mutation causes structural perturbations in TKD, reducing the catalytic activity of TKD. We conclude that loss-of-function mutations in FGFR1 cause nIHH with normal MRI of the olfactory system. These mutations also account for some of the mixed pedigrees, thus challenging the current idea that KS and nIHH are distinct entities.

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“…Genes encoding fibroblast growth factor 8 (FGF8) signalling pathway proteins, [17][18][19][20][21][22] chromodomain helicase DNA-binding protein 7 (CHD7) [23][24][25][26][27] and sex determining region Y-Box 10 (SOX10) 28,29 affect the neurogenic niche in the nasal area and craniofacial development. Conversely, Kallmann syndrome protein, which is now officially known as anosmin 1 (encoded by KAL1; following nomenclature change, the gene is now denoted as ANOS1), 2 prokineticin-2 and prokineticin receptor 2 (encoded by PROK2 and PROKR2, respectively), [30][31][32][33] WD repeat domain 11 (encoded by WDR11), 34,35 semaphorin 3A (encoded by SEMA3A) [36][37][38] and FEZ family zinc finger 1 (encoded by FEZF1) 39 influence migration of GnRH neurons.…”

Section: Biology Of the Gnrh Neuronal Systemmentioning

confidence: 99%

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

et al. 2015

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| Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ~50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRHsynthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ~10-20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.

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Developmental Regulation of Gonadotropin-Releasing Hormone Neurons by Fibroblast Growth Factor Signaling

Cited by 76 publications

References 57 publications

Novel Mechanisms of Fibroblast Growth Factor Receptor 1 Regulation by Extracellular Matrix Protein Anosmin-1

Novel Mechanisms of Fibroblast Growth Factor Receptor 1 Regulation by Extracellular Matrix Protein Anosmin-1

Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

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