RRC ID 36045
Author Abedini A, Zamberlam G, Lapointe E, Tourigny C, Boyer A, Paquet M, Hayashi K, Honda H, Kikuchi A, Price C, Boerboom D.
Title WNT5a is required for normal ovarian follicle development and antagonizes gonadotropin responsiveness in granulosa cells by suppressing canonical WNT signaling.
Journal FASEB J.
Abstract Whereas the roles of the canonical wingless-type MMTV (mouse mammary tumor virus) integration site family (WNT) signaling pathway in the regulation of ovarian follicle growth and steroidogenesis are now established, noncanonical WNT signaling in the ovary has been largely overlooked. Noncanonical WNTs, including WNT5a and WNT11, are expressed in granulosa cells (GCs) and are differentially regulated throughout follicle development, but their physiologic roles remain unknown. Using conditional gene targeting, we found that GC-specific inactivation ofWnt5a(but notWnt11) results in the female subfertility associated with increased follicular atresia and decreased rates of ovulation. Microarray analyses have revealed that WNT5a acts to down-regulate the expression of FSH-responsive genesin vitro, and corresponding increases in the expression of these genes have been found in the GCs of conditional knockout mice. Unexpectedly, we found that WNT5a regulates its target genes not by signalingviathe WNT/Ca(2+)or planar cell polarity pathways, but rather by inhibiting the canonical pathway, causing both β-catenin (CTNNB1) and cAMP responsive element binding (CREB) protein levels to decreaseviaa glycogen synthase kinase-3β-dependent mechanism. We further found that WNT5a prevents follicle-stimulating hormone and luteinizing protein from up-regulating the CTNNB1 and CREB proteins and their target genes, indicating that WNT5a functions as a physiologic inhibitor of gonadotropin signaling. Together, these findings identify WNT5a as a key regulator of follicle development and gonadotropin responsiveness.-Abedini, A., Zamberlam, G., Lapointe, E., Tourigny, C., Boyer, A., Paquet, M., Hayashi, K., Honda, H., Kikuchi, A., Price, C., Boerboom, D. WNT5a is required for normal ovarian follicle development and antagonizes gonadotropin responsiveness in granulosa cells by suppressing canonical WNT signaling.
Volume 30(4)
Pages 1534-47
Published 2016-4
DOI 10.1096/fj.15-280313
PII fj.15-280313
PMID 26667040
PMC PMC4799500
MeSH Animals Cells, Cultured Cyclic AMP Response Element-Binding Protein / genetics Cyclic AMP Response Element-Binding Protein / metabolism Female Gonadotropins / pharmacology* Granulosa Cells / drug effects* Granulosa Cells / metabolism Immunoblotting Immunohistochemistry Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Oligonucleotide Array Sequence Analysis Ovarian Follicle / cytology Ovarian Follicle / growth & development Ovarian Follicle / metabolism* Ovulation / drug effects Ovulation / genetics Reverse Transcriptase Polymerase Chain Reaction Transcriptome / drug effects Transcriptome / genetics Wnt Proteins / genetics* Wnt Proteins / metabolism Wnt Signaling Pathway / drug effects* Wnt Signaling Pathway / genetics Wnt-5a Protein
IF 5.595
Times Cited 1
WOS Category BIOLOGY BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY
Resource
Mice B6;129P2-Wnt5a<tm1.1Homy>(RBRC04609)