Loss of mitogen-activated protein kinase kinase kinase 4 (MAP3K4) reveals a requirement for MAPK signalling in mouse sex determination

Bogani, D., Siggers, P., Brixey, R., Warr, N., Beddow, S., Edwards, J., Williams, D., Wilhelm, D., Koopman, P., Flavell, R. A., Chi, H. B., Ostrer, H., Wells, S., Cheeseman, M. and Greenfield, A. (2009) Loss of mitogen-activated protein kinase kinase kinase 4 (MAP3K4) reveals a requirement for MAPK signalling in mouse sex determination. PLoS Biology, 7 9: e1000196-x. doi:10.1371/journal.pbio.1000196


Author Bogani, D.
Siggers, P.
Brixey, R.
Warr, N.
Beddow, S.
Edwards, J.
Williams, D.
Wilhelm, D.
Koopman, P.
Flavell, R. A.
Chi, H. B.
Ostrer, H.
Wells, S.
Cheeseman, M.
Greenfield, A.
Title Loss of mitogen-activated protein kinase kinase kinase 4 (MAP3K4) reveals a requirement for MAPK signalling in mouse sex determination
Journal name PLoS Biology   Check publisher's open access policy
ISSN 1544-9173
Publication date 2009-09-01
Year available 2009
Sub-type Article (original research)
DOI 10.1371/journal.pbio.1000196
Open Access Status DOI
Volume 7
Issue 9
Start page e1000196
End page x
Total pages 19
Editor Theodora Bloom
Place of publication San Francisco, CA., U.S.A.
Publisher Public Library of Science
Collection year 2010
Language eng
Subject C1
970106 Expanding Knowledge in the Biological Sciences
060403 Developmental Genetics (incl. Sex Determination)
Abstract Sex determination in mammals is controlled by the presence or absence of the Y-linked gene SRY. In the developing male (XY) gonad, sex-determining region of the Y (SRY) protein acts to up-regulate expression of the related gene, SOX9, a transcriptional regulator that in turn initiates a downstream pathway of testis development, whilst also suppressing ovary development. Despite the requirement for a number of transcription factors and secreted signalling molecules in sex determination, intracellular signalling components functioning in this process have not been defined. Here we report a role for the phylogenetically ancient mitogen-activated protein kinase (MAPK) signalling pathway in mouse sex determination. Using a forward genetic screen, we identified the recessive boygirl (byg) mutation. On the C57BL/6J background, embryos homozygous for byg exhibit consistent XY gonadal sex reversal. The byg mutation is an A to T transversion causing a premature stop codon in the gene encoding MAP3K4 (also known as MEKK4), a mitogen-activated protein kinase kinase kinase. Analysis of XY byg/byg gonads at 11.5 d post coitum reveals a growth deficit and a failure to support mesonephric cell migration, both early cellular processes normally associated with testis development. Expression analysis of mutant XY gonads at the same stage also reveals a dramatic reduction in Sox9 and, crucially, Sry at the transcript and protein levels. Moreover, we describe experiments showing the presence of activated MKK4, a direct target of MAP3K4, and activated p38 in the coelomic region of the XY gonad at 11.5 d post coitum, establishing a link between MAPK signalling in proliferating gonadal somatic cells and regulation of Sry expression. Finally, we provide evidence that haploinsufficiency for Map3k4 accounts for T-associated sex reversal (Tas). These data demonstrate that MAP3K4-dependent signalling events are required for normal expression of Sry during testis development, and create a novel entry point into the molecular and cellular mechanisms underlying sex determination in mice and disorders of sexual development in humans.
Keyword MESONEPHRIC CELL-MIGRATION
SEXUALLY DIMORPHIC EXPRESSION
STEROIDOGENIC FACTOR-I
TESTIS CORD FORMATION
SERTOLI-CELLS
GENE-EXPRESSION
TRANSCRIPTION FACTORS
OVARIAN DEVELOPMENT
PATTERNING DEFECTS
SOX9 EXPRESSION
Q-Index Code C1
Q-Index Status Confirmed Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
Institute for Molecular Bioscience - Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 59 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 24 Nov 2009, 01:26:14 EST