Foxl2 functions in sex determination and histogenesis throughout mouse ovary development.
BACKGROUND
Partial loss of function of the transcription factor FOXL2 leads to premature ovarian failure in women. In animal models, Foxl2 is required for maintenance, and possibly induction, of female sex determination independently of other critical genes, e.g., Rspo1. Here we report expression profiling of mouse ovaries that lack Foxl2 alone or in combination with Wnt4 or Kit/c-Kit.


RESULTS
Following Foxl2 loss, early testis genes (including Inhbb, Dhh, and Sox9) and several novel ovarian genes were consistently dysregulated during embryonic development. In the absence of Foxl2, expression changes affecting a large fraction of pathways were opposite those observed in Wnt4-null ovaries, reinforcing the notion that these genes have complementary actions in ovary development. Loss of one copy of Foxl2 revealed strong gene dosage sensitivity, with molecular anomalies that were milder but resembled ovaries lacking both Foxl2 alleles. Furthermore, a Foxl2 transgene disrupted embryonic testis differentiation and increased the levels of key female markers.


CONCLUSIONS
The results, including a comprehensive principal component analysis, 1) support the proposal of dose-dependent Foxl2 function and anti-testis action throughout ovary differentiation; and 2) identify candidate genes for roles in sex determination independent of FOXL2 (e.g., the transcription factors IRX3 and ZBTB7C) and in the generation of the ovarian reserve downstream of FOXL2 (e.g., the cadherin-domain protein CLSTN2 and the sphingomyelin synthase SGMS2). The gene inventory is a first step toward the identification of the full range of pathways with partly autonomous roles in ovary development, and thus provides a framework to analyze the genetic bases of female fertility.
Garcia-Ortiz
José Elias
JE
Laboratory of Genetics, NIA/NIH-IRP, Baltimore, MD, USA. egarcia@cucs.udg.mx
Pelosi
Emanuele
E
Omari
Shakib
S
Nedorezov
Timur
T
Piao
Yulan
Y
Karmazin
Jesse
J
Uda
Manuela
M
Cao
Antonio
A
Cole
Steve W
SW
Forabosco
Antonino
A
Schlessinger
David
D
Ottolenghi
Chris
C
D000818:Animals; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010053:Ovary / Q000196:embryology* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D025341:Principal Component Analysis; D019849:Sex Determination Processes; D013737:Testis / Q000196:embryology / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000502:physiology; D060528:Wnt4 Protein
D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C498893:Foxl2 protein, mouse; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse