Anosmin-1-Like Effect of UMODL1/Olfactorin on the Chemomigration of Mouse GnRH Neurons and Zebrafish Olfactory Axons Development

Elia Di Schiavi; Giulio Vistoli; Roberta Manuela Moretti; Ilaria Corrado; Giulia Zuccarini; Silvia Gervasoni; Lavinia Casati; Daniele Bottai; Giorgio Roberto Merlo; Roberto Maggi

doi:10.3389/fcell.2022.836179

Anosmin-1-Like Effect of UMODL1/Olfactorin on the Chemomigration of Mouse GnRH Neurons and Zebrafish Olfactory Axons Development

Front Cell Dev Biol. 2022 Feb 11:10:836179. doi: 10.3389/fcell.2022.836179. eCollection 2022.

Affiliations

¹ Institute of Biosciences and Bioresources, National Research Council of Italy, Naples, Italy.
² Department of Pharmaceutical Sciences DISFARM, Università degli Studi di Milano, Milano, Italy.
³ Department of Pharmacological and Biomolecular Sciences DISFEB, Università degli Studi di Milano, Milano, Italy.
⁴ Department Molecular Biotechnology and Health Science, University of Torino, Torino, Italy.

Abstract

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 omp ^2k :gap-CFP ^rw034 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.

Keywords: GnRH (gonadotropin-releasing hormone); UMODL1; anosmia; anosmin-1; development; hypothalamus and neuroendocrinology; olfactorin; olfactory axons.