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Transgenic expression of Map3k4 rescues T-associated sex reversal (Tas) in mice

Disorders of sex development in the human population range in severity from mild genital defects to gonadal sex reversal. XY female development has been associated with heterozygous mutations in several genes, including SOX9, WT1 and MAP3K1. In contrast, XY sex reversal in mice usually requires comp...

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Autores principales: Warr, Nick, Siggers, Pam, Carré, Gwenn-Aël, Bogani, Debora, Brixey, Rachel, Akiyoshi, Mika, Tachibana, Makoto, Teboul, Lydia, Wells, Sara, Sanderson, Jeremy, Greenfield, Andy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014197/
https://www.ncbi.nlm.nih.gov/pubmed/24452333
http://dx.doi.org/10.1093/hmg/ddu020
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author Warr, Nick
Siggers, Pam
Carré, Gwenn-Aël
Bogani, Debora
Brixey, Rachel
Akiyoshi, Mika
Tachibana, Makoto
Teboul, Lydia
Wells, Sara
Sanderson, Jeremy
Greenfield, Andy
author_facet Warr, Nick
Siggers, Pam
Carré, Gwenn-Aël
Bogani, Debora
Brixey, Rachel
Akiyoshi, Mika
Tachibana, Makoto
Teboul, Lydia
Wells, Sara
Sanderson, Jeremy
Greenfield, Andy
author_sort Warr, Nick
collection PubMed
description Disorders of sex development in the human population range in severity from mild genital defects to gonadal sex reversal. XY female development has been associated with heterozygous mutations in several genes, including SOX9, WT1 and MAP3K1. In contrast, XY sex reversal in mice usually requires complete absence of testis-determining gene products. One exception to this involves T-associated sex reversal (Tas), a phenomenon characterized by the formation of ovotestes or ovaries in XY mice hemizygous for the hairpin-tail (T(hp)) or T-Orleans (T(Orl)) deletions on proximal mouse chromosome 17. We recently reported that mice heterozygous for a null allele of Map3k4, which resides in the T(hp) deletion, exhibit XY ovotestis development and occasional gonadal sex reversal on the sensitized C57BL/6J-Y(AKR) (B6-Y(AKR)) genetic background, reminiscent of the Tas phenotype. However, these experiments did not exclude the possibility that loss of other loci in the T(hp) deletion, or other effects of the deletion itself, might contribute to Tas. Here, we show that disruption to Sry expression underlies XY gonadal defects in B6-Y(AKR) embryos harbouring the T(hp) deletion and that a functional Map3k4 bacterial artificial chromosome rescues these abnormalities by re-establishing a normal Sry expression profile. These data demonstrate that Map3k4 haploinsufficiency is the cause of T-associated sex reversal and that levels of this signalling molecule are a major determinant of the expression profile of Sry.
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spelling pubmed-40141972014-05-12 Transgenic expression of Map3k4 rescues T-associated sex reversal (Tas) in mice Warr, Nick Siggers, Pam Carré, Gwenn-Aël Bogani, Debora Brixey, Rachel Akiyoshi, Mika Tachibana, Makoto Teboul, Lydia Wells, Sara Sanderson, Jeremy Greenfield, Andy Hum Mol Genet Articles Disorders of sex development in the human population range in severity from mild genital defects to gonadal sex reversal. XY female development has been associated with heterozygous mutations in several genes, including SOX9, WT1 and MAP3K1. In contrast, XY sex reversal in mice usually requires complete absence of testis-determining gene products. One exception to this involves T-associated sex reversal (Tas), a phenomenon characterized by the formation of ovotestes or ovaries in XY mice hemizygous for the hairpin-tail (T(hp)) or T-Orleans (T(Orl)) deletions on proximal mouse chromosome 17. We recently reported that mice heterozygous for a null allele of Map3k4, which resides in the T(hp) deletion, exhibit XY ovotestis development and occasional gonadal sex reversal on the sensitized C57BL/6J-Y(AKR) (B6-Y(AKR)) genetic background, reminiscent of the Tas phenotype. However, these experiments did not exclude the possibility that loss of other loci in the T(hp) deletion, or other effects of the deletion itself, might contribute to Tas. Here, we show that disruption to Sry expression underlies XY gonadal defects in B6-Y(AKR) embryos harbouring the T(hp) deletion and that a functional Map3k4 bacterial artificial chromosome rescues these abnormalities by re-establishing a normal Sry expression profile. These data demonstrate that Map3k4 haploinsufficiency is the cause of T-associated sex reversal and that levels of this signalling molecule are a major determinant of the expression profile of Sry. Oxford University Press 2014-06-01 2014-01-22 /pmc/articles/PMC4014197/ /pubmed/24452333 http://dx.doi.org/10.1093/hmg/ddu020 Text en © The Author 2014. Published by Oxford University Press. http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Warr, Nick
Siggers, Pam
Carré, Gwenn-Aël
Bogani, Debora
Brixey, Rachel
Akiyoshi, Mika
Tachibana, Makoto
Teboul, Lydia
Wells, Sara
Sanderson, Jeremy
Greenfield, Andy
Transgenic expression of Map3k4 rescues T-associated sex reversal (Tas) in mice
title Transgenic expression of Map3k4 rescues T-associated sex reversal (Tas) in mice
title_full Transgenic expression of Map3k4 rescues T-associated sex reversal (Tas) in mice
title_fullStr Transgenic expression of Map3k4 rescues T-associated sex reversal (Tas) in mice
title_full_unstemmed Transgenic expression of Map3k4 rescues T-associated sex reversal (Tas) in mice
title_short Transgenic expression of Map3k4 rescues T-associated sex reversal (Tas) in mice
title_sort transgenic expression of map3k4 rescues t-associated sex reversal (tas) in mice
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014197/
https://www.ncbi.nlm.nih.gov/pubmed/24452333
http://dx.doi.org/10.1093/hmg/ddu020
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