BMP Signaling in the Human Fetal Ovary is Developmentally Regulated and Promotes Primordial Germ Cell Apoptosis  

Abstract

Primordial germ cells (PGCs) are the embryonic precursors of gametes in the adult organism, and their development, differentiation, and survival are regulated by a combination of growth factors collectively known as the germ cell niche. Although many candidate niche components have been identified through studies on mouse PGCs, the growth factor composition of the human PGC niche has not been studied extensively. Here we report a detailed analysis of the expression of components of the bone morphogenetic protein (BMP) signaling apparatus in the human fetal ovary, from postmigratory PGC proliferation to the onset of primordial follicle formation. We find developmentally regulated and reciprocal patterns of expression of BMP2 and BMP4 and identify germ cells to be the exclusive targets of ovarian BMP signaling. By establishing long-term cultures of human fetal ovaries in which PGCs are retained within their physiological niche, we find that BMP4 negatively regulates postmigratory PGC numbers in the human fetal ovary by promoting PGC apoptosis. Finally, we report expression of both muscle segment homeobox (MSX)1 and MSX2 in the human fetal ovary and reveal a selective upregulation of MSX2 expression in human fetal ovary in response to BMP4, suggesting this gene may act as a downstream effector of BMP-induced apoptosis in the ovary, as in other systems. These data reveal for the first time growth factor regulation of human PGC development in a physiologically relevant context and have significant implications for the development of cultures systems for the in vitro maturation of germ cells, and their derivation from pluripotent stem cells.

Msx1 and Msx2 promote meiosis initiation

“…This suggests a specific role for Msx in female meiosis. Msx1 and Msx2 are also expressed in the human foetal ovary, in accordance with a recent report identifying expression of MSX in the human ovary (Childs et al, 2010), indicating a conserved role for Msx in female mammalian germ cells. Cellsorting experiments, using Ssea-1 or Oct4-GFP, revealed high expression levels of Msx1 and Msx2 in mouse germ cells.…”

“…Bmp4 is required, during early development of the mouse embryo, for primordial germ cell generation (Lawson et al, 1999) and is later expressed, along with Bmp2 and Bmp7 (Ross et al, 2007), at 12.5 dpc in the ovary. Msx1 and Msx2 are clearly stimulated by Bmp2 and Bmp4 and represent the first Bmp-regulated factors during the gonad sex determination period in both mice (this study) and human (Childs et al, 2010). This might explain the sex-specific expression of Msx genes identified in the developing gonads.…”

“…Interestingly, expression of Bmp2, Bmp4 and Bmp7 increases in foetal mouse ovaries between 11.5 dpc and 13.5 dpc (Ross et al, 2007). Moreover, upregulation of MSX2 expression has recently been described following BMP4 treatment in the human foetal ovary in organotypic culture, and correlated with an increase in primordial germ cell apoptosis (Childs et al, 2010).…”

Ovarian adipocytokines are associated with early in vitro human embryo development independent of the action of ovarian insulin

“…There is evidence that both leptin and adiponectin receptors are expressed in the cumulus cells, and adiponectin receptors exhibit differential target gene expression profile in cumulus (CC) compared to granulosa cells (GC) [20,24]. One example of an interesting target gene is Bmp2, which has been implicated in follicular apoptosis and fetal germ cell differentiation in the ovary [6,10]. Adiponectin was found to upregulate the expression of Bmp2 in CCs [20], although whether the adiponectin Bmp2 interaction has a functional significance in vivo remains to be elucidated.…”

Molecular alterations during female reproductive aging: Can aged oocytes remind youth?

“…The PGCs proliferate rapidly, and approximately 7 × 10 6 oogonia are eventually formed at 6-8 weeks of gestation in humans. During this process, transforming growth factor- (TGF- family members, including activins, BMPs, and TGF-1, support the proliferation of PGCs (Godin & Wylie 1991;Richards et al 1999;Farini et al 2005;Childs et al 2010). Activins and their receptors are highly expressed in human oogonia at later stages of gestation and activin A supports the proliferation of oogonia in vitro (Martins da Silva et al 2004).…”