Developmentally regulated IL6-type cytokines signal to germ cells in the human fetal ovary

S L Eddie,A J Childs,H N Jabbour,R A Anderson

doi:10.1093/molehr/gar061

Abstract

Fetal ovarian development and primordial follicle formation are imperative for adult fertility in the female. Data suggest the interleukin (IL)6-type cytokines, leukaemia inhibitory factor (LIF), IL6, oncostatin M (OSM) and ciliary neurotrophic factor (CNTF), are able to regulate the survival, proliferation and differentiation of fetal murine germ cells (GCs) in vivo and in vitro. We postulated that these factors may play a similar role during early human GC development and primordial follicle formation. To test this hypothesis, we have investigated the expression and regulation of IL6-type cytokines, using quantitative reverse transcription polymerase chain reaction and immunohistochemistry. Expression of transcripts encoding OSM increased significantly across the gestational range examined (8-20 weeks), while expression of IL6 increased specifically between the first (8-11 weeks) and early second (12-16 weeks) trimesters, co-incident with the initiation of meiosis. LIF and CNTF expression remained unchanged. Expression of the genes encoding the LIF and IL6 receptors, and their common signalling subunit gp130, was also found to be developmentally regulated, with expression increasing significantly with increasing gestation. LIF receptor and gp130 proteins localized exclusively to GCs, including oocytes in primordial follicles, indicating this cell type to be the sole target of IL6-type cytokine signalling in the human fetal ovary. These data establish that IL6-type cytokines and their receptors are expressed in the human fetal ovary and may directly influence GC development at multiple stages of maturation.

Highlights

Fetal ovarian development is comprised of many complex processes, initiating with germ cell specification and migration to form the bi-potential gonad, followed by sex determination and entry to meiosis, culminating in primordial follicle formation (Edson et al, 2009)
To determine the presence and pattern of expression of mRNA transcripts encoding PGE2 precursor enzymes during human fetal ovarian development, qRT-polymerase chain reaction (PCR) was performed for COX1, COX2 and prostaglandin E synthase (PTGES) across a range of gestations
Ovarian specimens were grouped into three gestational stages to broadly reflect the key developmental events of early to mid-gestation ovarian development, namely the proliferation of undifferentiated primordial germ cells (PGCs) (8-11 weeks gestation), the formation of germ cell nests and entry of the first germ cells into meiosis (13-16 weeks), and on-going meiotic entry and the onset of primordial follicle formation (17-20 weeks)

Summary

Introduction

Fetal ovarian development is comprised of many complex processes, initiating with germ cell specification and migration to form the bi-potential gonad, followed by sex determination and entry to meiosis, culminating in primordial follicle formation (Edson et al, 2009). Brief characterisation of PROK expression was performed in the human testes when examining their possible function in testicular cancer (Samson et al, 2004) These studies determined PROK1 ligand is expressed in the Leydig cells of the adult testis rather than in the germ cells as demonstrated in the ovary in the previous chapter (LeCouter et al, 2003; Samson et al, 2004). Fetal ovarian development encompasses several highly regulated events, from initial germ cell specification and migration to the proximal epiblast in formation the gonad, followed by sex determination, entry into meiosis and subsequent arrest, and concluding in germ cell nest breakdown and association of oocytes with granulosa cells to form primordial follicles. This thesis encapsulates several studies that aimed to identify novel regulators of ovarian development, in an effort to further clarify what governs germ cell development and survival

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