Anosmin-1-Like Effect of UMODL1/Olfactorin on the Chemomigration of Mouse GnRH Neurons and Zebrafish Olfactory Axons Development
The impairment of development/migration of hypothalamic gonadotropin-releasing hormone (GnRH) neurons is the main cause of Kallmann's syndrome (KS), an inherited disorder characterized by hypogonadism, anosmia, and other developmental defects. Olfactorin is an extracellular matrix protein encod...
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Frontiers Media S.A.
2022-02-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2022.836179/full |
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| author | Elia Di Schiavi Giulio Vistoli Roberta Manuela Moretti Ilaria Corrado Giulia Zuccarini Silvia Gervasoni Lavinia Casati Daniele Bottai Giorgio Roberto Merlo Roberto Maggi |
| author_facet | Elia Di Schiavi Giulio Vistoli Roberta Manuela Moretti Ilaria Corrado Giulia Zuccarini Silvia Gervasoni Lavinia Casati Daniele Bottai Giorgio Roberto Merlo Roberto Maggi |
| author_sort | Elia Di Schiavi |
| collection | DOAJ |
| description | The impairment of development/migration of hypothalamic gonadotropin-releasing hormone (GnRH) neurons is the main cause of Kallmann's syndrome (KS), an inherited disorder characterized by hypogonadism, anosmia, and other developmental defects. Olfactorin is an extracellular matrix protein encoded by the UMODL1 (uromodulin-like 1) gene expressed in the mouse olfactory region along the migratory route of GnRH neurons. It shares a combination of WAP and FNIII repeats, expressed in complementary domains, with anosmin-1, the product of the ANOS1 gene, identified as the causative of KS. In the present study, we have investigated the effects of olfactorin in vitro and in vivo models. The results show that olfactorin exerts an anosmin-1-like strong chemoattractant effect on mouse-immortalized GnRH neurons (GN11 cells) through the activation of the FGFR and MAPK pathways. In silico analysis of olfactorin and anosmin-1 reveals a satisfactory similarity at the N-terminal region for the overall arrangement of corresponding WAP and FNIII domains and marked similarities between WAP domains’ binding modes of interaction with the resolved FGFR1–FGF2 complex. Finally, in vivo experiments show that the down-modulation of the zebrafish z-umodl1 gene (orthologous of UMODL1) in both GnRH3:GFP and omp2k:gap-CFPrw034 transgenic zebrafish strains leads to a clear disorganization and altered fasciculation of the neurites of GnRH3:GFP neurons crossing at the anterior commissure and a significant increase in olfactory CFP + fibers with altered trajectory. Thus, our study shows olfactorin as an additional factor involved in the development of olfactory and GnRH systems and proposes UMODL1 as a gene worthy of diagnostic investigation in KS. |
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| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-13T13:20:53Z |
| publishDate | 2022-02-01 |
| publisher | Frontiers Media S.A. |
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| spelling | doaj.art-b9ab0a64078c4dbab21b9331265e29002022-12-21T23:44:25ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2022-02-011010.3389/fcell.2022.836179836179Anosmin-1-Like Effect of UMODL1/Olfactorin on the Chemomigration of Mouse GnRH Neurons and Zebrafish Olfactory Axons DevelopmentElia Di Schiavi0Giulio Vistoli1Roberta Manuela Moretti2Ilaria Corrado3Giulia Zuccarini4Silvia Gervasoni5Lavinia Casati6Daniele Bottai7Giorgio Roberto Merlo8Roberto Maggi9Institute of Biosciences and Bioresources, National Research Council of Italy, Naples, ItalyDepartment of Pharmaceutical Sciences DISFARM, Università degli Studi di Milano, Milano, ItalyDepartment of Pharmacological and Biomolecular Sciences DISFEB, Università degli Studi di Milano, Milano, ItalyDepartment Molecular Biotechnology and Health Science, University of Torino, Torino, ItalyDepartment Molecular Biotechnology and Health Science, University of Torino, Torino, ItalyDepartment of Pharmaceutical Sciences DISFARM, Università degli Studi di Milano, Milano, ItalyDepartment of Pharmaceutical Sciences DISFARM, Università degli Studi di Milano, Milano, ItalyDepartment of Pharmaceutical Sciences DISFARM, Università degli Studi di Milano, Milano, ItalyDepartment Molecular Biotechnology and Health Science, University of Torino, Torino, ItalyDepartment of Pharmaceutical Sciences DISFARM, Università degli Studi di Milano, Milano, ItalyThe impairment of development/migration of hypothalamic gonadotropin-releasing hormone (GnRH) neurons is the main cause of Kallmann's syndrome (KS), an inherited disorder characterized by hypogonadism, anosmia, and other developmental defects. Olfactorin is an extracellular matrix protein encoded by the UMODL1 (uromodulin-like 1) gene expressed in the mouse olfactory region along the migratory route of GnRH neurons. It shares a combination of WAP and FNIII repeats, expressed in complementary domains, with anosmin-1, the product of the ANOS1 gene, identified as the causative of KS. In the present study, we have investigated the effects of olfactorin in vitro and in vivo models. The results show that olfactorin exerts an anosmin-1-like strong chemoattractant effect on mouse-immortalized GnRH neurons (GN11 cells) through the activation of the FGFR and MAPK pathways. In silico analysis of olfactorin and anosmin-1 reveals a satisfactory similarity at the N-terminal region for the overall arrangement of corresponding WAP and FNIII domains and marked similarities between WAP domains’ binding modes of interaction with the resolved FGFR1–FGF2 complex. Finally, in vivo experiments show that the down-modulation of the zebrafish z-umodl1 gene (orthologous of UMODL1) in both GnRH3:GFP and omp2k:gap-CFPrw034 transgenic zebrafish strains leads to a clear disorganization and altered fasciculation of the neurites of GnRH3:GFP neurons crossing at the anterior commissure and a significant increase in olfactory CFP + fibers with altered trajectory. Thus, our study shows olfactorin as an additional factor involved in the development of olfactory and GnRH systems and proposes UMODL1 as a gene worthy of diagnostic investigation in KS.https://www.frontiersin.org/articles/10.3389/fcell.2022.836179/fullGnRH (gonadotropin-releasing hormone)anosmin-1olfactorinUMODL1hypothalamus and neuroendocrinologyolfactory axons |
| spellingShingle | Elia Di Schiavi Giulio Vistoli Roberta Manuela Moretti Ilaria Corrado Giulia Zuccarini Silvia Gervasoni Lavinia Casati Daniele Bottai Giorgio Roberto Merlo Roberto Maggi Anosmin-1-Like Effect of UMODL1/Olfactorin on the Chemomigration of Mouse GnRH Neurons and Zebrafish Olfactory Axons Development Frontiers in Cell and Developmental Biology GnRH (gonadotropin-releasing hormone) anosmin-1 olfactorin UMODL1 hypothalamus and neuroendocrinology olfactory axons |
| title | Anosmin-1-Like Effect of UMODL1/Olfactorin on the Chemomigration of Mouse GnRH Neurons and Zebrafish Olfactory Axons Development |
| title_full | Anosmin-1-Like Effect of UMODL1/Olfactorin on the Chemomigration of Mouse GnRH Neurons and Zebrafish Olfactory Axons Development |
| title_fullStr | Anosmin-1-Like Effect of UMODL1/Olfactorin on the Chemomigration of Mouse GnRH Neurons and Zebrafish Olfactory Axons Development |
| title_full_unstemmed | Anosmin-1-Like Effect of UMODL1/Olfactorin on the Chemomigration of Mouse GnRH Neurons and Zebrafish Olfactory Axons Development |
| title_short | Anosmin-1-Like Effect of UMODL1/Olfactorin on the Chemomigration of Mouse GnRH Neurons and Zebrafish Olfactory Axons Development |
| title_sort | anosmin 1 like effect of umodl1 olfactorin on the chemomigration of mouse gnrh neurons and zebrafish olfactory axons development |
| topic | GnRH (gonadotropin-releasing hormone) anosmin-1 olfactorin UMODL1 hypothalamus and neuroendocrinology olfactory axons |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2022.836179/full |
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