Up-regulation of WNT-4 signaling and dosage-sensitive sex reversal in humans.
Date
2001-05ICR Author
Author
Jordan, BK
Mohammed, M
Ching, ST
Délot, E
Chen, XN
Dewing, P
Swain, A
Rao, PN
Elejalde, BR
Vilain, E
Type
Journal Article
Metadata
Show full item recordAbstract
Wnt-4, a member of the Wnt family of locally acting secreted growth factors, is the first signaling molecule shown to influence the sex-determination cascade. In mice, a targeted deletion of Wnt-4 causes the masculinization of XX pups. Therefore, WNT-4, the human homologue of murine Wnt-4, is a strong candidate gene for sex-reversal phenotypes in humans. In this article, we show that, in testicular Sertoli and Leydig cells, Wnt-4 up-regulates Dax1, a gene known to antagonize the testis-determining factor, Sry. Furthermore, we elucidate a possible mechanism for human XY sex reversal associated with a 1p31-p35 duplication including WNT-4. Overexpression of WNT-4 leads to up-regulation of DAX1, which results in an XY female phenotype. Thus, WNT-4, a novel sex-determining gene, and DAX1 play a concerted role in both the control of female development and the prevention of testes formation. These observations suggest that mammalian sex determination is sensitive to dosage, at multiple steps in its pathway.
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https://www.sciencedirect.com/science/article/pii/S0002929707612191?via=ihub#!Collections
Subject
Leydig Cells
Sertoli Cells
Cell Line
Chromosomes, Human, Pair 1
Fibroblasts
Animals
Humans
Mice
DNA-Binding Proteins
Proto-Oncogene Proteins
Receptors, Retinoic Acid
Transcription Factors
Repressor Proteins
In Situ Hybridization, Fluorescence
Transfection
Sequence Alignment
Signal Transduction
Up-Regulation
Amino Acid Sequence
Gene Dosage
Genes, Duplicate
Molecular Sequence Data
Female
Male
Wnt Proteins
DAX-1 Orphan Nuclear Receptor
Disorders of Sex Development
Sex Determination Processes
Wnt4 Protein
Research team
Development & Cancer
Language
eng
Date accepted
2001-03-13
License start date
2001-05
Citation
American journal of human genetics, 2001, 68 (5), pp. 1102 - 1109
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