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.
Highlights
Reproduction in mammals is under the control of a complex interaction of neuronal and hormonal factors
The modeling was focused on the N-terminal region comprising the first 700 residues of human and olfactorin that were aligned with the anosmin-1 sequence by NIH Cobalt (Papadopoulos and Agarwala, 2007) and used by Modeller (Webb and Sali, 2016) to generate the corresponding olfactorin structures
We demonstrate a chemotropic action of olfactorin on GN11 cells similar to the one exerted by anosmin-1 (Cariboni et al, 2004), and we show the involvement of heparan sulfate proteoglycans (HSPG) and fibroblast growth factor receptor (FGFR) in this response
Summary
Reproduction in mammals is under the control of a complex interaction of neuronal and hormonal factors. KS patients usually show low levels of circulating gonadotropins due to the impairment of the development and function of the GnRH neuronal system (Schwanzel-Fukuda et al, 1989; Cariboni and Maggi, 2006). KS is genetically highly heterogeneous, with more than 20 mutated genes identified and validated as the likely cause of the disease (Swee et al, 2021). ANOS1 was the first gene identified whose mutations, relatively frequent, cause the X-linked form of KS (Franco et al, 1991; De Castro et al, 2017). Immunocytochemical data consistently show that X-linked KS is due to an altered development of olfactory axons and migration of GnRH neurons (Schwanzel-Fukuda et al, 1989)
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