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Human RSPO1/R-spondin1 Is Expressed during Early Ovary Development and Augments beta-Catenin Signaling

Tomaselli, S; Megiorni, F; Lin, L; Mazzilli, MC; Gerrelli, D; Majore, S; Grammatico, P; (2011) Human RSPO1/R-spondin1 Is Expressed during Early Ovary Development and Augments beta-Catenin Signaling. PLOS ONE , 6 (1) , Article e16366. 10.1371/journal.pone.0016366. Green open access

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Abstract

Human testis development starts from around 42 days post conception with a transient wave of SRY expression followed by up-regulation of testis specific genes and a distinct set of morphological, paracrine and endocrine events. Although anatomical changes in the ovary are less marked, a distinct sub-set of ovary specific genes are also expressed during this time. The furin-domain containing peptide R-spondin1 (RSPO1) has recently emerged as an important regulator of ovary development through up-regulation of the WNT/beta-catenin pathway to oppose testis formation. Here, we show that RSPO1 is upregulated in the ovary but not in the testis during critical early stages of gonad development in humans (between 6-9 weeks post conception), whereas the expression of the related genes WNT4 and CTNNB1 (encoding beta catenin) is not significantly different between these tissues. Furthermore, reduced R-spondin1 function in the ovotestis of an individual (46,XX) with a RSPO1 mutation leads to reduced beta-catenin protein and WNT4 mRNA levels, consistent with down regulation of ovarian pathways. Transfection of wildtype RSPO1 cDNA resulted in weak dose-dependent activation of a beta-catenin responsive TOPFLASH reporter (1.8 fold maximum), whereas co-transfection of CTNNB1 (encoding beta-catenin) with RSPO1 resulted in dose-dependent synergistic augmentation of this reporter (approximately 10 fold). Furthermore, R-spondin1 showed strong nuclear localization in several different cell lines. Taken together, these data show that R-spondin1 is upregulated during critical stages of early human ovary development and may function as a tissue-specific amplifier of beta-catenin signaling to oppose testis determination.

Type: Article
Title: Human RSPO1/R-spondin1 Is Expressed during Early Ovary Development and Augments beta-Catenin Signaling
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0016366
Publisher version: http://dx.doi.org/10.1371/journal.pone.0016366
Language: English
Additional information: © 2011 Tomaselli et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. JCA is a Wellcome Trust Senior Fellow in Clinical Science [079666]. The Human Developmental Biology Resource receives funding from the Medical Research Council [G0700089] and The Wellcome Trust [082557]. This work was partially supported by a grant from MIUR (COFIN 2008 CAP7245/1) and by the Auriga ONLUS project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: SEX DETERMINATION REVEALS, GENE-EXPRESSION, R-SPONDIN, GONADAL DEVELOPMENT, ADULT OVARIES, R-SPONDIN1, DIFFERENTIATION, REVERSAL, RSPO1, ACTIVATION
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1058176
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