Abstract
BackgroundR-spondin2 (Rspo2) is a secreted agonist of the canonical Wnt/β-catenin signaling pathway. Rspo2 plays a key role in development of limbs, lungs and hair follicles, and more recently during ovarian follicle development. Rspo2 heterozygous deficient female mice become infertile around 4 months of age mimicking primary ovarian insufficiency (POI). The study aimed to investigate the regulation of RSPO2 and its potential involvement in pathophysiology of POI.MethodsWe cloned the RSPO2 promoter and performed transcriptional assays to determine if RSPO2 can be regulated by NOBOX, an ovarian transcription factor. Then, we evaluated 100 infertile women after obtaining a detailed history of the disease and follicle-stimulating hormone measurements, besides karyotype determination and fragile-X premutation syndrome investigation. All exons, intron-exon boundaries and untranslated regions of the RSPO2 gene were identified by sequencing, and the results were statistically analyzed.ResultsWe found that RSPO2 can be regulated by NOBOX via the presence of NOBOX Binding Element in its promoter. Among 9 identified variants in POI women, 4 of them were equally homozygous, 4 have never been described (c.-359C > G, c.-190G > A, c.-170 + 13C > T and c.-169-8 T > A), only one c.557 T > C was predicted to alter a single amino acid in the RSPO2 protein (p.Leu186Pro).ConclusionsRSPO2 is a novel target gene of the NOBOX key transcription factor, confirming its important role during the follicular growth in ovary. However, RSPO2 mutations are rare or uncommon in women with POI.
Highlights
R-spondin2 (Rspo2) is a secreted agonist of the canonical Wnt/β-catenin signaling pathway
RSPO2 is a novel target gene of NOBOX The ovarian Rspo2 expression was reported very low in Nobox-null mice suggesting that it is controlled by this transcription factor [22]
In silico analysis of Rspo2 promoter revealed the presence of two NOBOX Binding Element (NBE) (Fig. 1a)
Summary
R-spondin (Rspo2) is a secreted agonist of the canonical Wnt/β-catenin signaling pathway. Rspo heterozygous deficient female mice become infertile around 4 months of age mimicking primary ovarian insufficiency (POI). Primary Ovarian Insufficiency (POI) is an important human disease model that provided substantial understanding into the factors involved in differentiation and ovarian development. This rare disease is characterized by amenorrhea with elevated gonadotropin levels, and affects 1% of women before the age of 40 years [1]. It has recently been suggested that Rspo, another member of this family, could be important in regulating ovarian follicle development [14]. Rspo heterozygous deficient female mice become infertile around 4 months of age, mimicking POI [15,16,17]
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