FOXL2 is a female sex-determining gene in the goat.
The origin of sex reversal in XX goats homozygous for the polled intersex syndrome (PIS) mutation was unclear because of the complexity of the mutation that affects the transcription of both FOXL2 and several long noncoding RNAs (lncRNAs). Accumulating evidence suggested that FOXL2 could be the sole gene of the PIS locus responsible for XX sex reversal, the lncRNAs being involved in transcriptional regulation of FOXL2. In this study, using zinc-finger nuclease-directed mutagenesis, we generated several fetuses, of which one XX individual bears biallelic mutations of FOXL2. Our analysis demonstrates that FOXL2 loss of function dissociated from loss of lncRNA expression is sufficient to cause an XX female-to-male sex reversal in the goat model and, as in the mouse model, an agenesis of eyelids. Both developmental defects were reproduced in two newborn animals cloned from the XX FOXL2(-/-) fibroblasts. These results therefore identify FOXL2 as a bona fide female sex-determining gene in the goat. They also highlight a stage-dependent role of FOXL2 in the ovary, different between goats and mice, being important for fetal development in the former but for postnatal maintenance in the latter.
INRA, UMR 1198 Biologie du Développement et Reproduction, 78350 Jouy-en-Josas, France.
Laurent
L
Boulanger
INRA, UMR 1198 Biologie du Développement et Reproduction, 78350 Jouy-en-Josas, France.
Maëlle
M
Pannetier
INRA, UMR 1198 Biologie du Développement et Reproduction, 78350 Jouy-en-Josas, France.
Laurence
L
Gall
INRA, UMR 1198 Biologie du Développement et Reproduction, 78350 Jouy-en-Josas, France.
Aurélie
A
Allais-Bonnet
INRA, UMR 1198 Biologie du Développement et Reproduction, 78350 Jouy-en-Josas, France.
Maëva
M
Elzaiat
INRA, UMR 1198 Biologie du Développement et Reproduction, 78350 Jouy-en-Josas, France; UNCEIA R&D, 13 Rue Jouët, 94704 Maisons-Alfort, France.
Daniel
D
Le Bourhis
INRA, UMR 1198 Biologie du Développement et Reproduction, 78350 Jouy-en-Josas, France.
Nathalie
N
Daniel
INRA, UMR 1198 Biologie du Développement et Reproduction, 78350 Jouy-en-Josas, France.
Christophe
C
Richard
INRA, UMR 1198 Biologie du Développement et Reproduction, 78350 Jouy-en-Josas, France.
Corinne
C
Cotinot
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U964, CNRS UMR 7104, University of Strasbourg (UdS), Department of Functional Genomics and Cancer, 1 Rue Laurent Fries, BP10142, 67404 Illkirch Cedex, France.
Norbert B
NB
Ghyselinck
INRA, UMR 1198 Biologie du Développement et Reproduction, 78350 Jouy-en-Josas, France. Electronic address: eric.pailhoux@jouy.inra.fr.
Eric
E
Pailhoux
D000818:Animals; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006041:Goats / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D008297:Male; D010053:Ovary / Q000196:embryology / Q000378:metabolism; D019849:Sex Determination Processes; D013737:Testis / Q000196:embryology / Q000378:metabolism; D014960:X Chromosome; D014998:Y Chromosome
D051858:Forkhead Transcription Factors