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FGF9 and WNT4 act as antagonistic signals to regulate mammalian sex determination

Kim, Y; Kobayashi, A; Sekido, R; DiNapoli, L; Brennan, J; Chaboissier, M-C; Poulat, F; ... Capel, B; + view all (2006) FGF9 and WNT4 act as antagonistic signals to regulate mammalian sex determination. PLoS Biology , 4 (6) , Article e187. 10.1371/journal.pbio.0040187. Green open access

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Abstract

The genes encoding members of the wingless-related MMTV integration site (WNT) and fibroblast growth factor (FGF) families coordinate growth, morphogenesis, and differentiation in many fields of cells during development. In the mouse, Fgf9 and Wnt4 are expressed in gonads of both sexes prior to sex determination. Loss of Fgf9 leads to XY sex reversal, whereas loss of Wnt4 results in partial testis development in XX gonads. However, the relationship between these signals and the male sex-determining gene, Sry, was unknown. We show through gain- and loss-of-function experiments that fibroblast growth factor 9 (FGF9) and WNT4 act as opposing signals to regulate sex determination. In the mouse XY gonad, Sry normally initiates a feed-forward loop between Sox9 and Fgf9, which up-regulates Fgf9 and represses Wnt4 to establish the testis pathway. Surprisingly, loss of Wnt4 in XX gonads is sufficient to up-regulate Fgf9 and Sox9 in the absence of Sry. These data suggest that the fate of the gonad is controlled by antagonism between Fgf9 and Wnt4. The role of the male sex-determining switch— Sry in the case of mammals—is to tip the balance between these underlying patterning signals. In principle, sex determination in other vertebrates may operate through any switch that introduces an imbalance between these two signaling pathways.

Type: Article
Title: FGF9 and WNT4 act as antagonistic signals to regulate mammalian sex determination
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pbio.0040187
Publisher version: http://dx.doi.org/10.1371/journal.pbio.0040187
Language: English
Additional information: © 2006 Kim 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. Funding: This work was funded by grants from the National Institutes of Health to BC (HD39963), and to RRB (HD30284).
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 Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/58929
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