Alternative splicing of the mouse embryonic poly(A) binding protein (Epab) mRNA is regulated by an exonic splicing enhancer: a model for post-transcriptional control of gene expression in the oocyte

Embryonic poly(A) binding protein (EPAB), expressed in oocytes and early embryos, binds and stabilizes maternal mRNAs, and mediates initiation of their translation. We identified an alternatively spliced form of Epab lacking exon 10 (c.Ex10del) and investigated the regulation of Epab mRNA alternative splicing as a model for alternative splicing in oocytes and early preimplantation embryos. Specifically, we evaluated the following mechanisms: imprinting; RNA editing and exonic splicing enhancers (ESEs). Sequence analysis led to the identification of two single nucleotide polymorphisms (SNPs): one was detected in exon 9 (rs55858A/G), and served as a marker for the parental origin of the alternatively spliced form, and the other was found in exon 10 (rs56574G/C), and co-segregated with the exon 9 SNP. We found that the presence of rs56574G in exon 10 led to the formation of an ESE, leading to efficient exclusion of exon 10. Real-time RT–PCR results revealed a 5-fold increase in the expression of the c.Ex10del alternative splicing variant in animals carrying rs56574G/G in exon 10 compared with rs56574C/C at the same locus. Our findings suggest that SNPs may alter the ratio between alternative splicing variants of oocyte-specific proteins. The role that these subtle differences play in determining individual reproductive outcome remains to be determined

Understanding how space travel affects the female reproductive system to the Moon and beyond

As the space industry grows exponentially and aspirations for space travel expand, we are entering a new era where we will very likely become an interplanetary species. Although reproduction is an essential human function and necessary for species survival, we have remarkably little knowledge regarding the impact of space travel on the female reproductive system. The effects of spaceflight on human reproductive potential, fertility, implantation and subsequent pregnancy resulting in a healthy live birth must be considered before planning prolonged spaceflight missions and the colonization of planets. In this review, we explore what is known and what remains to be learned about the effects of space travel on female reproductive endocrinology. We also delve deeper into reproductive endocrinology and discuss normal physiologic mechanisms at the molecular level to have a better understanding of how it may change during spaceflight. The rigors of spaceflight including radiation, gravitational stressors, and circadian rhythm changes could potentially affect ovulation, fertilization, endometrial receptivity, preimplantation embryo development, embryo implantation, placentation, and pregnancy. Thus, we will examine what is known about spaceflight effects on the hypothalamic–pituitary–gonadal (HPG) axis, ovarian folliculogenesis and steroidogenesis, early embryogenesis, endometrial receptivity, and pregnancy. We further discuss the recent advances in reproductive endocrinology and future research platforms. Establishing a better understanding of the effect of space travel on female reproductive health, as well as developing countermeasures to mitigate adverse effects, are decisive components of our species’ successful transition to an interplanetary one

Human Endometrial CD98 Is Essential for Blastocyst Adhesion

BACKGROUND: Understanding the molecular basis of embryonic implantation is of great clinical and biological relevance. Little is currently known about the adhesion receptors that determine endometrial receptivity for embryonic implantation in humans. METHODS AND PRINCIPAL FINDINGS: Using two human endometrial cell lines characterized by low and high receptivity, we identified the membrane receptor CD98 as a novel molecule selectively and significantly associated with the receptive phenotype. In human endometrial samples, CD98 was the only molecule studied whose expression was restricted to the implantation window in human endometrial tissue. CD98 expression was restricted to the apical surface and included in tetraspanin-enriched microdomains of primary endometrial epithelial cells, as demonstrated by the biochemical association between CD98 and tetraspanin CD9. CD98 expression was induced in vitro by treatment of primary endometrial epithelial cells with human chorionic gonadotropin, 17-β-estradiol, LIF or EGF. Endometrial overexpression of CD98 or tetraspanin CD9 greatly enhanced mouse blastocyst adhesion, while their siRNA-mediated depletion reduced the blastocyst adhesion rate. CONCLUSIONS: These results indicate that CD98, a component of tetraspanin-enriched microdomains, appears to be an important determinant of human endometrial receptivity during the implantation window

Ectopic Pregnancy as a Model to Identify Endometrial Genes and Signaling Pathways Important in Decidualization and Regulated by Local Trophoblast

The endometrium in early pregnancy undergoes decidualization and functional changes induced by local trophoblast, which are not fully understood. We hypothesized that endometrium from tubal ectopic pregnancy (EP) could be interrogated to identify novel genes and pathways involved in these processes. Gestation-matched endometrium was collected from women with EP (n = 11) and intrauterine pregnancies (IUP) (n = 13). RNA was extracted from the tissue. In addition, tissues were prepared for histological analysis for degree of decidualization. We compared a) the samples from EP that were decidualized (n = 6) with non-decidualized samples (n = 5), and b) the decidualized EP (n = 6) with decidualization-matched IUP (n = 6) samples using an Affymetrix gene array platform, with Ingenuity Pathway Analysis, combined with quantitative RT-PCR. Expression of PRL and IGFBP1 was used to confirm the degree of decidualization in each group. There were no differences in PRL or IGFBP1 expression in the decidualization-matched samples but a marked reduction (P<0.001) in the non-decidualized samples. Decidualization was associated with increased expression of 428 genes including SCARA5 (181-fold), DKK1 (71-fold) and PROK1 (32-fold), and decreased expression of 230 genes including MMP-7 (35-fold) and SFRP4 (21-fold). The top canonical pathways associated with these differentially expressed genes were Natural Killer Cell and Wnt/b-Catenin signaling. Local trophoblast was associated with much less alteration of endometrial gene expression with an increase in 56 genes, including CSH1 (8-fold), and a reduction in 29 genes including CRISP3 (8-fold). The top associated canonical pathway was Antigen Presentation. The study of endometrium from tubal EP may promote novel insights into genes involved in decidualization and those influenced by factors from neighboring trophoblast. This has afforded unique information not highlighted by previous studies and adds to our understanding of the endometrium in early pregnancy

From Fertilisation to Implantation in Mammalian Pregnancy-Modulation of Early Human Reproduction by the Endocannabinoid System.

There is an increasing recognition that the endocannabinoid system is the crucial cytokine-hormone system regulating early human pregnancy. The synchronous development of the fertilized embryo and the endometrium to ensure timely implantation has been shown to be one of the pivotal steps to successful implantation. This development is thought to be regulated by a finely balanced relationship between various components of the endocannabinoid system in the endometrium, the embryo and the Fallopian tube. In addition, this system has also been shown to be involved in the regulation of the development and maturation of the gametes prior to fertilization. In this review, we will examine the evidence from animal and human studies to support the role of the endocannabinoid system in gametogenesis, fertilization, implantation, early pregnancy maintenance, and in immunomodulation of pregnancy. We will discuss the role of the cannabinoid receptors and the enzymes involved in the synthesis and degradation of the key endocannabinoid ligands (e.g., anandamide and 2-arachinoylglycerol) in early reproduction

Integrative multi-omics module network inference with Lemon-Tree

Module network inference is an established statistical method to reconstruct co-expression modules and their upstream regulatory programs from integrated multi-omics datasets measuring the activity levels of various cellular components across different individuals, experimental conditions or time points of a dynamic process. We have developed Lemon-Tree, an open-source, platform-independent, modular, extensible software package implementing state-of-the-art ensemble methods for module network inference. We benchmarked Lemon-Tree using large-scale tumor datasets and showed that Lemon-Tree algorithms compare favorably with state-of-the-art module network inference software. We also analyzed a large dataset of somatic copy-number alterations and gene expression levels measured in glioblastoma samples from The Cancer Genome Atlas and found that Lemon-Tree correctly identifies known glioblastoma oncogenes and tumor suppressors as master regulators in the inferred module network. Novel candidate driver genes predicted by Lemon-Tree were validated using tumor pathway and survival analyses. Lemon-Tree is available from http://lemon-tree.googlecode.com under the GNU General Public License version 2.0.Comment: minor revision; 13 pages text + 4 figures + 4 tables + 4 pages supplementary methods; supplementary tables available from the author