Excess DAX1 leads to XY ovotesticular disorder of sex development (DSD) in mice by inhibiting steroidogenic factor-1 (SF1) activation of the testis enhancer of SRY-box-9 (Sox9)

Ludbrook, Louisa M., Bernard, Pascal, Bagheri-Fam, Stefan, Ryan, Janelle, Sekido, Ryohei, Wilhelm, Dagmar, Lovell-Badge, Robin and Harley, Vincent R. (2012) Excess DAX1 leads to XY ovotesticular disorder of sex development (DSD) in mice by inhibiting steroidogenic factor-1 (SF1) activation of the testis enhancer of SRY-box-9 (Sox9). Endocrinology, 153 4: 1948-1958. doi:10.1210/en.2011-1428


Author Ludbrook, Louisa M.
Bernard, Pascal
Bagheri-Fam, Stefan
Ryan, Janelle
Sekido, Ryohei
Wilhelm, Dagmar
Lovell-Badge, Robin
Harley, Vincent R.
Title Excess DAX1 leads to XY ovotesticular disorder of sex development (DSD) in mice by inhibiting steroidogenic factor-1 (SF1) activation of the testis enhancer of SRY-box-9 (Sox9)
Journal name Endocrinology   Check publisher's open access policy
ISSN 0013-7227
1945-7170
Publication date 2012-04
Sub-type Article (original research)
DOI 10.1210/en.2011-1428
Volume 153
Issue 4
Start page 1948
End page 1958
Total pages 11
Place of publication Chevy Chase, MD, United States
Publisher The Endocrine Society
Collection year 2013
Language eng
Formatted abstract
Human DAX1 duplications cause dosage-sensitive sex reversal (DSS) whereby chromosomally XY individuals can develop as females due to gonadal dysgenesis. However, the mechanism of DSSadrenal hypoplasia congenita on X, gene 1 (DAX1) action in the fetal testis is unknown. We show that in fetal testes from XY  Dax1-overexpressing transgenic mice, the expression of the key testispromoting
gene sex-determining region on Y (SRY)-box-9 (Sox9) is reduced. Moreover, in XY Sox9 heterozygotes, in which testis development is usually normal, Dax1 overexpression results in ovotestes, suggesting a DAX1-SOX9 antagonism. The ovarian portion of the XY ovotestes was characterized by expression of the granulosa cell marker, Forkhead box-L2, with complete loss of the Sertoli cell markers, SOX9 and anti-Müllerian hormone, and the Leydig cell marker CYP17A1.  However, the expression ofSRYandsteroidogenic factor-1 (SF1),twokey transcriptional regulators
of Sox9, was retained in the ovarian portion of the XY ovotestes. Using reporter mice, Dax1 overexpression reduced activation of TES, the testis enhancer of Sox9, indicating that DAX1 might repress Sox9 expression via TES. In cultured cells, increasing levels of DAX1 antagonized SF1-, SF1/SRY-, and SF1/SOX9-mediated activation of TES, due to reduced binding of SF1 to TES, providing a likely mechanism for DSS.
Keyword Pre-Sertoli Cells
Sry-Related Gene
Wilms-Tumor 1
Gonadal Development
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online before print January 31, 2012,

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
Institute for Molecular Bioscience - Publications
 
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