The Experts below are selected from a list of 381 Experts worldwide ranked by ideXlab platform
Pierremarc Bouloux - One of the best experts on this subject based on the ideXlab platform.
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X-linked GnRH deficiency: role of KAL-1 mutations in GnRH deficiency.
Molecular and Cellular Endocrinology, 2011Co-Authors: Pierremarc BoulouxAbstract:The gene for X-linked Kallmann's syndrome (KAL-1, encoding Anosmin-1) was cloned in 1991. Over a decade elapsed before autosomal forms of KS and most of other genetic forms of isolated hypogonadotrophic hypogonadism (IHH) became characterized, and the genetic diversity of these disorders fully appreciated. Although KAL-1 mutations appear to cause a more severe reproductive phenotype than other IHH genes, the biology of this multidomain extracellular matrix protein has only been partially characterized. Initial studies suggested a central role of Anosmin-1, in GnRH neuron ontogeny - specifically in GnRH neuronal migration from the cribriform plate area into the brain - as well as in olfactory bulb development. Anosmin-1 is expressed extracellularly, with high affinity binding to cell membrane heparan sulphate proteoglycans. It is expressed in the outer layers of the developing olfactory bulb, the neuroretina, the cerebellum, spinal cord and developing kidney. Recent observations have demonstrated an Anosmin-1 heparan sulphate dependent functional interaction with the product of the autosomal dominant KAL-2 (FGFR1: anosmin-2) gene, thereby modulating FGFR1 signalling. Although these genes are frequently co-expressed in developing tissues, this may not represent the sole mode of action of Anosmin-1, and FGFR1 independent actions of the protein have also been identified. Structural and in vitro functional studies have shown that Anosmin-1 may have complex biological actions. Anosmin-1 interactions with FGFR1 have however been best characterized and represent the dominant focus of this chapter.
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novel mechanisms of fibroblast growth factor receptor 1 regulation by extracellular matrix protein anosmin 1
Journal of Biological Chemistry, 2009Co-Authors: Scott E Guimond, Paul J Travers, Steven Mark Cadman, Erhard Hohenester, Jeremy E Turnbull, Soohyun Kim, Pierremarc BoulouxAbstract: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 isoform-specific 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 FGF2.heparin complex, thus preventing FGFR1.FGF2.heparin complex formation. By contrast, heparin-bound Anosmin-1 binds to pre-formed FGF2.FGFR1 complex, generating an Anosmin-1.FGFR1.FGF2.heparin 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 FGFR1.FGF2.heparin complex.
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eLS - Insights into the Molecular Basis of Kallman Syndrome
Encyclopedia of Life Sciences, 2007Co-Authors: Soohyun Kim, Steven Mark Cadman, Pierremarc BoulouxAbstract:Kallmann syndrome (KS) consists of anosmia related to defective olfactory bulb development and hypogonadotrophic hypogonadism due to gonadotrophin-releasing hormone (GnRH) deficiency. Two genes have been identified so far: KAL-1, encoding Anosmin-1, and KAL-2,encoding fibroblast growth factor receptor 1 (FGFR1). Keywords: Kallmann syndrome; hypogonadotrophic hypogonadism; Anosmin-1; fibroblast growth factor receptor 1
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Molecular Pathogenesis of Kallmanns Syndrome
2007Co-Authors: Steven Mark Cadman, Soohyun Kim, David González-martínez, Pierremarc BoulouxAbstract:Hypogonadotrophic hypogonadism (HH) is characterized by delayed or absent pubertal development secondary to gonadotrophin deficiency. HH can result from mutations of the gonadotrophin-releasing hormone receptor 1, the gonadotrophin -subunits, or various transcription factors involved in pituitary gland development. HH occurs in DAX1 mutations when associated with adrenal insufficiency (adrenal hypoplasia congenita), and is also linked with obesity in patients with mutations of leptin and its receptor, as well as mutations in prohormone convertase 1. Rarely, HH has resulted from kisspeptin receptor (GPR54) mutations, a gene implicated in the regulation of pubertal onset. When occurring with anosmia (a lack of sense of smell), HH is referred to as Kallmann’s syndrome (KS). Two KS-related loci are currently known: KAL1 , encoding Anosmin-1, responsible for Xlinked KS, and KAL2 , encoding the fibroblast growth factor receptor 1 (FGFR1), mutated in autosomal dominant KS. Anosmin-1 is an extracellular glycoprotein with some unique structural characteristics; it interacts with both urokinasetype plasminogen activator and FGFR1. It has previously been shown that Anosmin-1 enhances FGFR1 signalling in a heparan sulphate-dependent manner, and proposed that Published online: December 21, 2006 HORMONE RESEARCH Steven Cadman Centre for Neuroendocrinology, Royal Free and University College Medical School Rowland Hill Street London NW3 2PF (UK) Tel. +44 020 7433 2879, Fax +44 020 7433 2871, E Mail s.cadman@medsch.ucl.ac.uk © 2007 S. Karger AG, Basel 0301–0163/07/0675–0231$23.50/0 Accessible online at: www.karger.com/hre D ow nl oa de d by : 15 7. 55 .3 9. 42 4 /2 1/ 20 16 7 :5 1: 26 A M
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anosmin 1 modulates fibroblast growth factor receptor 1 signaling in human gonadotropin releasing hormone olfactory neuroblasts through a heparan sulfate dependent mechanism
The Journal of Neuroscience, 2004Co-Authors: David Gonzalezmartinez, Scott E Guimond, Jeremy E Turnbull, Soohyun Kim, Jonathan Schofield, Paul Winyard, Gabriella B Vannelli, Pierremarc BoulouxAbstract:Defects of either Anosmin-1 or fibroblast growth factor receptor 1 (FGFR1) are known to underlie hereditary Kallmann9s syndrome (KS), a human disorder of olfactory and gonadotropin-releasing hormone (GnRH) neuronal ontogeny. Here, we report a functional interaction between Anosmin-1 and the FGFR1-FGF2-heparan sulfate complex, leading to amplified responses in the FGFR1 signaling pathway. In human embryonic GnRH olfactory neuroblasts, wild-type Anosmin-1, but not proteins with loss-of-function KS mutations, induces neurite outgrowth and cytoskeletal rearrangements through FGFR1-dependent mechanisms involving p42/44 and p38 mitogen-activated protein kinases and Cdc42/Rac1 activation. Furthermore, Anosmin-1 enhances FGF2 signaling specifically through FGFR1 IIIc in heterologous BaF3 lymphoid cells in a heparan sulfate-dependent manner. Our study provides compelling evidence for Anosmin-1 as an isoform-specific co-ligand modulator of FGFR signaling that amplifies and specifies FGFR1 signaling responses during human nervous system development and defines a mechanism underlying the link between autosomal and X-linked KS.
Jean-pierre Hardelin - One of the best experts on this subject based on the ideXlab platform.
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Kallmann syndrome
European Journal of Human Genetics, 2009Co-Authors: Catherine Dode, Jean-pierre HardelinAbstract:The Kallmann syndrome (KS) combines hypogonadotropic hypogonadism (HH) with anosmia. This is a clinically and genetically heterogeneous disease. KAL1, encoding the extracellular glycoprotein Anosmin-1, is responsible for the X chromosome-linked recessive form of the disease. Mutations in FGFR1 or FGF8 , encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, respectively, underlie an autosomal dominant form with incomplete penetrance. Finally, mutations in PROKR2 and PROK2 , encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous, and compound heterozygous states. These two genes are likely to be involved both in monogenic recessive and digenic/oligogenic KS transmission modes. Notably, mutations in any of the above-mentioned KS genes have been found in less than 30% of the KS patients, which indicates that other genes involved in the disease remain to be discovered.
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The complex genetics of Kallmann syndrome: KAL1, FGFR1, FGF8, PROKR2, PROK2, et al.
Sexual Development, 2008Co-Authors: Jean-pierre Hardelin, Catherine DodeAbstract:Kallmann syndrome (KS) combines hypogonadotropic hypogonadism and anosmia. Anosmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to gonadotropin-releasing hormone (GnRH) deficiency, which presumably results from a failure of the embryonic migration of neuroendocrine GnRH cells from the olfactory epithelium to the forebrain. This failure could be a consequence of the early degeneration of olfactory nerve and terminal nerve fibres, because the latter normally act as guiding cues for the migration of GnRH cells. Defects in GnRH cell fate specification, differentiation, axon elongation or axon targeting to the hypothalamus median eminence may, however, also contribute to GnRH deficiency, at least in some genetic forms of the disease. To date, five KS genes have been identified, namely, FGFR1, FGF8, PROKR2, PROK2, and KAL1. Mutations in these genes, however, account for barely 30% of all KS cases. Mutations in FGFR1, encoding fibroblast growth factor receptor 1, underlie an autosomal dominant form of the disease. Mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous or compound heterozygous states. These two genes are likely to be involved both in monogenic recessive and digenic or oligogenic KS transmission modes. Finally, KAL1, encoding the extracellular glycoprotein Anosmin-1, is responsible for the X chromosome-linked form of the disease. It is believed that Anosmin-1 acts as an enhancer of FGF signalling and perhaps of prokineticin signalling too.
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Kallmann syndrome: fibroblast growth factor signaling insufficiency?
Journal of Molecular Medicine, 2004Co-Authors: Catherine Dode, Jean-pierre HardelinAbstract:Kallmann syndrome (KAL) is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Anosmia is related to the absence or hypoplasia of the olfactory bulbs. Hypogonadism is due to GnRH deficiency and is likely to result from the failed embryonic migration of GnRH-synthesizing neurons. These cells normally migrate from the olfactory epithelium to the forebrain along the olfactory nerve pathway. KAL is phenotypically and genetically heterogeneous. The gene responsible for the X-chromosome linked form of the disease (KAL1) has been identified in 1991. KAL1 encodes Anosmin-1, an approx. 95-kDa glycoprotein of unknown function which is present locally in various extracellular matrices during the period of organogenesis. The recent finding that FGFR1 mutations are involved in an autosomal dominant form of Kallmann syndrome (KAL2), combined with the analysis of mutant mouse embryos that no longer express Fgfr1 in the telencephalon, suggests that the disease results from a deficiency in FGF signaling at the earliest stage of olfactory bulb morphogenesis. We propose that the role of Anosmin-1 is to enhance FGF signaling and suggest that the gender difference in Anosmin-1 dose (because KAL1 partially escapes X-inactivation) explains the higher prevalence of the disease in males.
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x chromosome linked kallmann syndrome clinical heterogeneity in three siblings carrying an intragenic deletion of the kal 1 gene
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: N Massin, Jean-pierre Hardelin, Catherine Dode, Christophe Pecheux, Corinne Eloit, Jeanlouis Bensimon, Julie Galey, F Kuttenn, P TouraineAbstract:Kallmann syndrome (KS) is characterized by the association of hypogonadotropic hypogonadism and anosmia. The gene underlying the X chromosome-linked form of the disease, KAL-1, consists of 14 coding exons. It encodes a glycoprotein, Anosmin-1, which is involved in the embryonic migration of GnRH-synthesizing neurons and the differentiation of the olfactory bulbs. We describe herein the clinical heterogeneity in three affected brothers who carry a large deletion (exons 3–13) in KAL-1. All three had a history of hypogonadotropic hypogonadism with delayed puberty. Although brain magnetic resonance imaging showed hypoplastic olfactory bulbs in the three siblings, variable degrees of anosmia/hyposmia were shown by olfactometry. In addition, these brothers had different phenotypic anomalies, i.e. unilateral renal aplasia (siblings B and C), high-arched palate (sibling A), brachymetacarpia (sibling A), mirror movements (siblings A and B), and abnormal eye movements (sibling C). Last but not least, sibling A suff...
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x chromosome linked kallmann syndrome clinical heterogeneity in three siblings carrying an intragenic deletion of the kal 1 gene
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: N Massin, Jean-pierre Hardelin, Catherine Dode, Christophe Pecheux, Corinne Eloit, Jeanlouis Bensimon, Julie Galey, F Kuttenn, P TouraineAbstract:Kallmann syndrome (KS) is characterized by the association of hypogonadotropic hypogonadism and anosmia. The gene underlying the X chromosome-linked form of the disease, KAL-1, consists of 14 coding exons. It encodes a glycoprotein, Anosmin-1, which is involved in the embryonic migration of GnRH-synthesizing neurons and the differentiation of the olfactory bulbs. We describe herein the clinical heterogeneity in three affected brothers who carry a large deletion (exons 3-13) in KAL-1. All three had a history of hypogonadotropic hypogonadism with delayed puberty. Although brain magnetic resonance imaging showed hypoplastic olfactory bulbs in the three siblings, variable degrees of anosmia/hyposmia were shown by olfactometry. In addition, these brothers had different phenotypic anomalies, i.e. unilateral renal aplasia (siblings B and C), high-arched palate (sibling A), brachymetacarpia (sibling A), mirror movements (siblings A and B), and abnormal eye movements (sibling C). Last but not least, sibling A suffered from a severe congenital hearing impairment, a feature that had been reported in KS but had not yet been ascribed unambiguously to the X-linked form of the disease. The variable phenotype, both qualitatively and quantitatively, in this family further emphasizes the role of putative modifier genes, and/or epigenetic factors, in the expressivity of the X-linked KS.
Catherine Dode - One of the best experts on this subject based on the ideXlab platform.
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Kallmann syndrome
European Journal of Human Genetics, 2009Co-Authors: Catherine Dode, Jean-pierre HardelinAbstract:The Kallmann syndrome (KS) combines hypogonadotropic hypogonadism (HH) with anosmia. This is a clinically and genetically heterogeneous disease. KAL1, encoding the extracellular glycoprotein Anosmin-1, is responsible for the X chromosome-linked recessive form of the disease. Mutations in FGFR1 or FGF8 , encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, respectively, underlie an autosomal dominant form with incomplete penetrance. Finally, mutations in PROKR2 and PROK2 , encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous, and compound heterozygous states. These two genes are likely to be involved both in monogenic recessive and digenic/oligogenic KS transmission modes. Notably, mutations in any of the above-mentioned KS genes have been found in less than 30% of the KS patients, which indicates that other genes involved in the disease remain to be discovered.
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The complex genetics of Kallmann syndrome: KAL1, FGFR1, FGF8, PROKR2, PROK2, et al.
Sexual Development, 2008Co-Authors: Jean-pierre Hardelin, Catherine DodeAbstract:Kallmann syndrome (KS) combines hypogonadotropic hypogonadism and anosmia. Anosmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to gonadotropin-releasing hormone (GnRH) deficiency, which presumably results from a failure of the embryonic migration of neuroendocrine GnRH cells from the olfactory epithelium to the forebrain. This failure could be a consequence of the early degeneration of olfactory nerve and terminal nerve fibres, because the latter normally act as guiding cues for the migration of GnRH cells. Defects in GnRH cell fate specification, differentiation, axon elongation or axon targeting to the hypothalamus median eminence may, however, also contribute to GnRH deficiency, at least in some genetic forms of the disease. To date, five KS genes have been identified, namely, FGFR1, FGF8, PROKR2, PROK2, and KAL1. Mutations in these genes, however, account for barely 30% of all KS cases. Mutations in FGFR1, encoding fibroblast growth factor receptor 1, underlie an autosomal dominant form of the disease. Mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous or compound heterozygous states. These two genes are likely to be involved both in monogenic recessive and digenic or oligogenic KS transmission modes. Finally, KAL1, encoding the extracellular glycoprotein Anosmin-1, is responsible for the X chromosome-linked form of the disease. It is believed that Anosmin-1 acts as an enhancer of FGF signalling and perhaps of prokineticin signalling too.
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Kallmann syndrome: fibroblast growth factor signaling insufficiency?
Journal of Molecular Medicine, 2004Co-Authors: Catherine Dode, Jean-pierre HardelinAbstract:Kallmann syndrome (KAL) is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Anosmia is related to the absence or hypoplasia of the olfactory bulbs. Hypogonadism is due to GnRH deficiency and is likely to result from the failed embryonic migration of GnRH-synthesizing neurons. These cells normally migrate from the olfactory epithelium to the forebrain along the olfactory nerve pathway. KAL is phenotypically and genetically heterogeneous. The gene responsible for the X-chromosome linked form of the disease (KAL1) has been identified in 1991. KAL1 encodes Anosmin-1, an approx. 95-kDa glycoprotein of unknown function which is present locally in various extracellular matrices during the period of organogenesis. The recent finding that FGFR1 mutations are involved in an autosomal dominant form of Kallmann syndrome (KAL2), combined with the analysis of mutant mouse embryos that no longer express Fgfr1 in the telencephalon, suggests that the disease results from a deficiency in FGF signaling at the earliest stage of olfactory bulb morphogenesis. We propose that the role of Anosmin-1 is to enhance FGF signaling and suggest that the gender difference in Anosmin-1 dose (because KAL1 partially escapes X-inactivation) explains the higher prevalence of the disease in males.
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x chromosome linked kallmann syndrome clinical heterogeneity in three siblings carrying an intragenic deletion of the kal 1 gene
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: N Massin, Jean-pierre Hardelin, Catherine Dode, Christophe Pecheux, Corinne Eloit, Jeanlouis Bensimon, Julie Galey, F Kuttenn, P TouraineAbstract:Kallmann syndrome (KS) is characterized by the association of hypogonadotropic hypogonadism and anosmia. The gene underlying the X chromosome-linked form of the disease, KAL-1, consists of 14 coding exons. It encodes a glycoprotein, Anosmin-1, which is involved in the embryonic migration of GnRH-synthesizing neurons and the differentiation of the olfactory bulbs. We describe herein the clinical heterogeneity in three affected brothers who carry a large deletion (exons 3–13) in KAL-1. All three had a history of hypogonadotropic hypogonadism with delayed puberty. Although brain magnetic resonance imaging showed hypoplastic olfactory bulbs in the three siblings, variable degrees of anosmia/hyposmia were shown by olfactometry. In addition, these brothers had different phenotypic anomalies, i.e. unilateral renal aplasia (siblings B and C), high-arched palate (sibling A), brachymetacarpia (sibling A), mirror movements (siblings A and B), and abnormal eye movements (sibling C). Last but not least, sibling A suff...
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x chromosome linked kallmann syndrome clinical heterogeneity in three siblings carrying an intragenic deletion of the kal 1 gene
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: N Massin, Jean-pierre Hardelin, Catherine Dode, Christophe Pecheux, Corinne Eloit, Jeanlouis Bensimon, Julie Galey, F Kuttenn, P TouraineAbstract:Kallmann syndrome (KS) is characterized by the association of hypogonadotropic hypogonadism and anosmia. The gene underlying the X chromosome-linked form of the disease, KAL-1, consists of 14 coding exons. It encodes a glycoprotein, Anosmin-1, which is involved in the embryonic migration of GnRH-synthesizing neurons and the differentiation of the olfactory bulbs. We describe herein the clinical heterogeneity in three affected brothers who carry a large deletion (exons 3-13) in KAL-1. All three had a history of hypogonadotropic hypogonadism with delayed puberty. Although brain magnetic resonance imaging showed hypoplastic olfactory bulbs in the three siblings, variable degrees of anosmia/hyposmia were shown by olfactometry. In addition, these brothers had different phenotypic anomalies, i.e. unilateral renal aplasia (siblings B and C), high-arched palate (sibling A), brachymetacarpia (sibling A), mirror movements (siblings A and B), and abnormal eye movements (sibling C). Last but not least, sibling A suffered from a severe congenital hearing impairment, a feature that had been reported in KS but had not yet been ascribed unambiguously to the X-linked form of the disease. The variable phenotype, both qualitatively and quantitatively, in this family further emphasizes the role of putative modifier genes, and/or epigenetic factors, in the expressivity of the X-linked KS.
Fernando Castro - One of the best experts on this subject based on the ideXlab platform.
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the adhesion molecule anosmin 1 in neurology kallmann syndrome and beyond
Advances in neurobiology, 2014Co-Authors: Fernando Castro, Veronica Murciabelmonte, Pedro F. Esteban, Diego Garciagonzalez, Ana Bribian, Diego ClementeAbstract:Anosmin-1 is the glycoprotein encoded by the KAL1 gene and part of the extracellular matrix, which was first identified as defective in human Kallmann syndrome (KS, characterised by hypogonadotropic hypogonadism and anosmia); biochemically it is a cell adhesion protein. The meticulous biochemical dissection of the Anosmin-1 domains has identified which domains are necessary for the protein to bind its different partners to display its biological effects. Research in the last decade has unravelled different roles of Anosmin-1 during CNS development (axon pathfinding, axonal collateralisation, cell motility and migration), some of them intimately related with the cited KS but not only with this. More recently, Anosmin-1 has been identified in other pathological scenarios both within (multiple sclerosis) and outside (cancer, atopic dermatitis) the CNS.
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ERK1/2 signaling is essential for the chemoattraction exerted by human FGF2 and human Anosmin-1 on newborn rat and mouse OPCs via FGFR1.
Glia, 2013Co-Authors: Verónica Murcia-belmonte, Ana Bribian, Fernando Castro, E. M. Medina-rodríguez, Pedro F. EstebanAbstract:Signaling through fibroblast growth factor receptors (FGFRs) is essential for many cellular processes including proliferation and migration, as well as differentiation events such as myelination. Anosmin-1 is an extracellular matrix (ECM) glycoprotein that interacts with the fibroblast growth factor receptor 1 (FGFR1) to exert its biological actions through this receptor, although the intracellular pathways underlying Anosmin-1 signaling remain largely unknown. This protein is defective in the X-linked form of Kallmann syndrome (KS) and has a prominent role in the migration of neuronal and oligodendroglial precursors. We have shown that Anosmin-1 exerts a chemotactic effect via FGFR1 on neuronal precursors from the subventricular zone (SVZ) and the essential role of the ERK1/2 signaling. We report here the positive chemotactic effect of FGF2 and Anosmin-1 on rat and mouse postnatal OPCs via FGFR1. The same effect was observed with the truncated N-terminal region of Anosmin-1 (A1Nt). The introduction in Anosmin-1 of the missense mutation F517L found in patients suffering from KS annulled the chemotactic activity; however, the mutant form carrying the disease-causing mutation E514K also found in KS patients, behaved as the wild-type protein. The chemoattraction exhibited by FGF2 and Anosmin-1 on OPCs was blocked by the mitogen-activated protein kinase (MAPK) inhibitor U0126, suggesting that the activation of the ERK1/2 MAPK signaling pathway following interaction with the FGFR1 is necessary for FGF2 and Anosmin-1 to exert their chemotactic effect. In fact, both proteins were able to induce the phosphorylation of the ERK1/2 kinases after the activation of the FGFR1 receptor. GLIA 2014;62:374–386
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The cysteine-rich region and the whey acidic protein domain are essential for Anosmin-1 biological functions.
Journal of neurochemistry, 2012Co-Authors: Pedro F. Esteban, Verónica Murcia-belmonte, Diego García-gonzález, Fernando CastroAbstract:The protein Anosmin-1, coded by the KAL1 gene responsible for the X-linked form of Kallmann syndrome (KS), exerts its biological effects mainly through the interaction with and signal modulation of fibroblast growth factor receptor 1 (FGFR1). We have previously shown the interaction of the third fibronectin-like type 3 (FnIII) domain and the N-terminal region of Anosmin-1 with FGFR1. Here, we demonstrate that missense mutations reported in patients with KS, C172R and N267K did not alter or substantially reduce, respectively, the binding to FGFR1. These substitutions annulled the chemoattraction of the full-length protein over subventricular zone (SVZ) neuronal precursors (NPs), but they did not annul it in the N-terminal-truncated protein (A1Nt). We also show that although not essential for binding to FGFR1, the cysteine-rich (CR) region is necessary for Anosmin-1 function and that FnIII.3 cannot substitute for FnIII.1 function. Truncated proteins recapitulating nonsense mutations found in KS patients did not show the chemotropic effect on SVZ NPs, suggesting that the presence behind FnIII.1 of any part of Anosmin-1 produces an unstable protein incapable of action. We also identify the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway as necessary for the chemotropic effect exerted by FGF2 and Anosmin-1 on rat SVZ NPs.
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FGF-2 and Anosmin-1 Are Selectively Expressed in Different Types of Multiple Sclerosis Lesions
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011Co-Authors: Diego Clemente, María Cristina Ortega, F. J. Arenzana, Fernando CastroAbstract:Multiple sclerosis is a demyelinating disease that affects ∼2,000,000 people worldwide. In the advanced stages of the disease, endogenous oligodendrocyte precursors cannot colonize the lesions or differentiate into myelinating oligodendrocytes. During development, both FGF-2 and Anosmin-1 participate in oligodendrocyte precursor cell migration, acting via the FGF receptor 1 (FGFR1). Hence, we performed a histopathological and molecular analysis of these developmental modulators in postmortem tissue blocks from multiple sclerosis patients. Accordingly, we demonstrate that the distribution of FGF-2 and Anosmin-1 varies between the different types of multiple sclerosis lesions: FGF-2 is expressed only within active lesions and in the periplaque of chronic lesions, whereas Anosmin-1 is upregulated within chronic lesions and is totally absent in active lesions. We show that the endogenous oligodendrocyte precursor cells recruited toward chronic-active lesions express FGFR1, possibly in response to the FGF-2 produced by microglial cells in the periplaque. Also in human tissue, FGF-2 is upregulated in perivascular astrocytes in regions of the normal-appearing gray matter, where the integrity of the blood–brain barrier is compromised. In culture, FGF-2 and Anosmin-1 influence adult mouse oligodendrocyte precursor cell migration in the same manner as at embryonic stages, providing an explanation for the histopathological observations: FGF-2 attracts/enhances its migration, which is hindered by Anosmin-1. We propose that FGF-2 and Anosmin-1 are markers for the histopathological type and the level of inflammation of multiple sclerosis lesions, and that they may serve as novel pharmacogenetic targets to design future therapies that favor effective remyelination and protect the blood–brain barrier.
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Biochemical dissection of Anosmin-1 interaction with FGFR1 and components of the extracellular matrix.
Journal of neurochemistry, 2010Co-Authors: Verónica Murcia-belmonte, Pedro F. Esteban, Diego García-gonzález, Fernando CastroAbstract:J. Neurochem. (2010) 115, 1256–1265. Abstract Anosmin-1, defective in Kallmann’s syndrome, participates in the adhesion, migration and differentiation of different cell types in the CNS. Although not fully understood, the mechanisms of action of Anosmin-1 involve the interaction with different proteins, being the interaction with fibroblast growth factor receptor 1 (FGFR1) and the modulation of its signalling the best studied to date. Using glutathione-S-transferase pull-down assays we demonstrate that the FnIII.3 (Fibronectin-like type III) domain and the combination whey acidic protein-FnIII.1, but not each of them individually, interact with FGFR1. The interaction of the whey acidic protein-FnIII.1 domains is substantially reduced when the cysteine-rich region is present, suggesting a likely regulatory role for this domain. The introduction in FnIII.3 of any of the two missense mutations found in Kallmann’s syndrome patients, E514K and F517L, abolished the interaction with FGFR1, what suggests an important role for these residues in the interaction. Interestingly, the chemoattraction of Anosmin-1 on rat neuronal precursors (NPs) via FGFR1 is retained by the N-terminal region of Anosmin-1 but not by FnIII.3 alone, and is lost in proteins carrying either one of the missense mutations, probably because of a highly reduced binding capacity to FGFR1. We also describe homophilic interaction Anosmin-1/Anosmin-1 via the FnIII repeats 1 and 4, and the interaction of FnIII.1 and FnIII.3 with Fibronectin and of FnIII.3 with Laminin.
Pedro F. Esteban - One of the best experts on this subject based on the ideXlab platform.
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anosmin 1 over expression increases adult neurogenesis in the subventricular zone and neuroblast migration to the olfactory bulb
Brain Structure & Function, 2016Co-Authors: Diego Garciagonzalez, Veronica Murciabelmonte, Pedro F. Esteban, Felipe Ortega, David Diaz, Irene Sanchezvera, Rafael Lebrongalan, Laura Escobarcastanondo, Luis Martinezmillan, Eduardo WeruagaAbstract:New subventricular zone (SVZ)-derived neuroblasts that migrate via the rostral migratory stream are continuously added to the olfactory bulb (OB) of the adult rodent brain. Anosmin-1 (A1) is an extracellular matrix protein that binds to FGF receptor 1 (FGFR1) to exert its biological effects. When mutated as in Kallmann syndrome patients, A1 is associated with severe OB morphogenesis defects leading to anosmia and hypogonadotropic hypogonadism. Here, we show that A1 over-expression in adult mice strongly increases proliferation in the SVZ, mainly with symmetrical divisions, and produces substantial morphological changes in the normal SVZ architecture, where we also report the presence of FGFR1 in almost all SVZ cells. Interestingly, for the first time we show FGFR1 expression in the basal body of primary cilia in neural progenitor cells. Additionally, we have found that A1 over-expression also enhances neuroblast motility, mainly through FGFR1 activity. Together, these changes lead to a selective increase in several GABAergic interneuron populations in different OB layers. These specific alterations in the OB would be sufficient to disrupt the normal processing of sensory information and consequently alter olfactory memory. In summary, this work shows that FGFR1-mediated A1 activity plays a crucial role in the continuous remodelling of the adult OB
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Anosmin 1 Interacts with the Prokineticin Receptor 2 In Vitro Indicating a Molecular Link Between Both Proteins in the Pathogenesis of Kallmann Syndrome.
Protein and peptide letters, 2016Co-Authors: Verónica Murcia-belmonte, Verónica Astillero-lópez, Pedro F. EstebanAbstract:Sexual maturation and olfactory bulb defects found in prokineticin 2 (Pk2) and prokineticin receptor 2 (Pkr2) mutant mice resembling the phenotypic characteristics of Kallmann syndrome (KS), gave rise to the question of whether these genes would have a role in KS pathogenesis. Later, mutations in both genes were identified in patients suffering from KS. The gene responsible for the Xlinked form of KS, ANOS1, encodes the ECM protein anosmin 1. Among other functions, anosmin 1 can regulate the activity of FGFR1, encoded by one of the genes involved in the autosomal transmission of KS. Therefore, it has been proposed that anosmin 1 could interact with PKR2 to modulate its activity. We present the first evidence supporting this hypothesis and report the interaction of full-length anosmin 1 with three extracellular domains of PKR2. A truncated anosmin 1 protein comprising the first three domains of the protein interacts with the second extracellular loop of PKR2, involved in PK2 binding. Finally, last three FnIII repeats of anosmin 1 also interacted with the PKR2 domains that interacted with full-length anosmin 1. Our data represent a molecular link between two of the genes involved in KS pathogenesis.
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the adhesion molecule anosmin 1 in neurology kallmann syndrome and beyond
Advances in neurobiology, 2014Co-Authors: Fernando Castro, Veronica Murciabelmonte, Pedro F. Esteban, Diego Garciagonzalez, Ana Bribian, Diego ClementeAbstract:Anosmin-1 is the glycoprotein encoded by the KAL1 gene and part of the extracellular matrix, which was first identified as defective in human Kallmann syndrome (KS, characterised by hypogonadotropic hypogonadism and anosmia); biochemically it is a cell adhesion protein. The meticulous biochemical dissection of the Anosmin-1 domains has identified which domains are necessary for the protein to bind its different partners to display its biological effects. Research in the last decade has unravelled different roles of Anosmin-1 during CNS development (axon pathfinding, axonal collateralisation, cell motility and migration), some of them intimately related with the cited KS but not only with this. More recently, Anosmin-1 has been identified in other pathological scenarios both within (multiple sclerosis) and outside (cancer, atopic dermatitis) the CNS.
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ERK1/2 signaling is essential for the chemoattraction exerted by human FGF2 and human Anosmin-1 on newborn rat and mouse OPCs via FGFR1.
Glia, 2013Co-Authors: Verónica Murcia-belmonte, Ana Bribian, Fernando Castro, E. M. Medina-rodríguez, Pedro F. EstebanAbstract:Signaling through fibroblast growth factor receptors (FGFRs) is essential for many cellular processes including proliferation and migration, as well as differentiation events such as myelination. Anosmin-1 is an extracellular matrix (ECM) glycoprotein that interacts with the fibroblast growth factor receptor 1 (FGFR1) to exert its biological actions through this receptor, although the intracellular pathways underlying Anosmin-1 signaling remain largely unknown. This protein is defective in the X-linked form of Kallmann syndrome (KS) and has a prominent role in the migration of neuronal and oligodendroglial precursors. We have shown that Anosmin-1 exerts a chemotactic effect via FGFR1 on neuronal precursors from the subventricular zone (SVZ) and the essential role of the ERK1/2 signaling. We report here the positive chemotactic effect of FGF2 and Anosmin-1 on rat and mouse postnatal OPCs via FGFR1. The same effect was observed with the truncated N-terminal region of Anosmin-1 (A1Nt). The introduction in Anosmin-1 of the missense mutation F517L found in patients suffering from KS annulled the chemotactic activity; however, the mutant form carrying the disease-causing mutation E514K also found in KS patients, behaved as the wild-type protein. The chemoattraction exhibited by FGF2 and Anosmin-1 on OPCs was blocked by the mitogen-activated protein kinase (MAPK) inhibitor U0126, suggesting that the activation of the ERK1/2 MAPK signaling pathway following interaction with the FGFR1 is necessary for FGF2 and Anosmin-1 to exert their chemotactic effect. In fact, both proteins were able to induce the phosphorylation of the ERK1/2 kinases after the activation of the FGFR1 receptor. GLIA 2014;62:374–386
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The cysteine-rich region and the whey acidic protein domain are essential for Anosmin-1 biological functions.
Journal of neurochemistry, 2012Co-Authors: Pedro F. Esteban, Verónica Murcia-belmonte, Diego García-gonzález, Fernando CastroAbstract:The protein Anosmin-1, coded by the KAL1 gene responsible for the X-linked form of Kallmann syndrome (KS), exerts its biological effects mainly through the interaction with and signal modulation of fibroblast growth factor receptor 1 (FGFR1). We have previously shown the interaction of the third fibronectin-like type 3 (FnIII) domain and the N-terminal region of Anosmin-1 with FGFR1. Here, we demonstrate that missense mutations reported in patients with KS, C172R and N267K did not alter or substantially reduce, respectively, the binding to FGFR1. These substitutions annulled the chemoattraction of the full-length protein over subventricular zone (SVZ) neuronal precursors (NPs), but they did not annul it in the N-terminal-truncated protein (A1Nt). We also show that although not essential for binding to FGFR1, the cysteine-rich (CR) region is necessary for Anosmin-1 function and that FnIII.3 cannot substitute for FnIII.1 function. Truncated proteins recapitulating nonsense mutations found in KS patients did not show the chemotropic effect on SVZ NPs, suggesting that the presence behind FnIII.1 of any part of Anosmin-1 produces an unstable protein incapable of action. We also identify the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway as necessary for the chemotropic effect exerted by FGF2 and Anosmin-1 on rat SVZ NPs.