The boygirl (byg) mouse mutant reveals that MAP3K4-mediated signaling is necessary for normal SRY expression and testis specification in the developing mouse gonad

A Beverdam

A Gazel

A Hammes

A Jacquel

A. G Kayali

A. M Clark

A. M Winter-Vann

A. N Abell

Andy Greenfield

B Capel

B Moniot

B. D Cuevas

B. M Cattanach

C Ottolenghi

C Tilmann

C. S Raymond

D Schmidt

D Wilhelm

D. R Johnson

Dagmar Wilhelm

Debbie Williams

Debora Bogani

E Wright

E. A Mann

E. M Eicher

E. M Prager

F Barrionuevo

F Charron

F Gao

G. D Hammer

G. J Bouma

H Chi

H Hotokezaka

H Ostrer

H. H Yao

Harry Ostrer

Hongbo Chi

I Dan

I. R Adams

J Bowles

J Brennan

J Cocquet

J Gubbay

J Karl

J Koubova

J Martineau

J Schlessinger

J Schmahl

J. C Achermann

J. J Meeks

J. M Park

J. R Hawkins

J. S Colvin

Jessica Edwards

K Jeays-Ward

K Kitamura

K. A Loffler

K. H Albrecht

L Chi

L Marsh

L Smith

L. A Casselton

L. L Washburn

M Bullejos

M Desclozeaux

M Feldbrugge

M Fernandez-Tome

M Matsuyama

M Takekawa

M Uda

M Uzumcu

M. C Chaboissier

M. J Bitgood

M. J Wilson

M. K Thomsen

Michael Cheeseman

N Warr

N. A Arango

N. D Hastie

Nick Warr

P Gerwins

P Koopman

P Siggers

P. M Humpert

PLoS Biology

English

PubMed

Pam Siggers

Rachel Brixey

Sarah Beddow

Peter Koopman

Richard A. Flavell

Sara Wells

Robin Lovell-Badge

R Lovell-Badge

Y Kim

S Bagheri-Fam

S. G Tevosian

Y Katoh-Fukui

S Nef

S Cui

S. Y Park

Y Qin

S Grimmond

R Sekido

S Malki

S. T Bradford

R Hiramatsu

S. P Davies

Crossref

Loss of Mitogen-Activated Protein Kinase Kinase Kinase 4 (MAP3K4) Reveals a Requirement for MAPK Signalling in Mouse Sex Determination

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.</p

Bogani, Debora

Siggers, Pam

Brixey, Rachel

Warr, Nick

Beddow, Sarah

Edwards, Jessica

Williams, Debbie

Wilhelm, Dagmar

Koopman, Peter

Flavell, Richard A.

Chi, Hongbo

Ostrer, Harry

Wells, Sara

Cheeseman, Michael

Greenfield, Andy

Edinburgh Research Explorer

Bogani Debora

Siggers Pam

Brixey Rachel

Warr Nick

Beddow Sarah

Edwards Jessica

Williams Debbie

Wilhelm Dagmar

Koopman Peter

Flavell Richard A.

Chi Hongbo

Ostrer Harry

Wells Sara

Cheeseman Michael

Greenfield Andy

Public Library of Science (PLOS)

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

Bogani, D

Siggers, P

Brixey, R

Warr, N

Beddow, S

Edwards, J

Williams, D

Wilhelm, D

Koopman, P

Flavell, RA

Chi, H

Ostrer, H

Wells, S

Cheeseman, M

Greenfield, A

University of Melbourne Institutional Repository

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

CiteSeerX

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

Richard A Flavell

Directory of Open Access Journals

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.

Greenfield, A.

University of Queensland eSpace

Warr, Nicholas

Flavell, Richard

Wells, Mary

Monash University Research Repository

http://minerva-access.unimelb.edu.au/bitstream/11343/209029/1/Loss%20of%20mitogen-activated%20protein%20kinase%20kinase%20kinase%204%20%28MAP3K4%29%20reveals%20a%20requirement%20for%20MAPK%20signalling%20in%20mouse%20sex%20determination.pdf

Loss of Mitogen-Activated Protein Kinase Kinase Kinase 4 (MAP3K4) Reveals a Requirement for MAPK Signalling in Mouse Sex Determination

Abstract

Similar works

Full text

Available Versions