GDF9 is transiently expressed in oocytes before follicle formation in the human fetal ovary and is regulated by a novel NOBOX transcript.

During human fetal ovary development, the process of primordial follicle formation is immediately preceded by a highly dynamic period of germ cell and somatic cell reorganisation. This is regulated by germ-cell specific transcription regulators, by the conserved RNA binding proteins DAZL and BOLL and by secreted growth factors of the TGFβ family, including activin βA: these all show changing patterns of expression preceding follicle formation. In mice, the transcription factor Nobox is essential for follicle formation and oocyte survival, and NOBOX regulates the expression of GDF9 in humans.

BMP signaling in the human fetal ovary is developmentally regulated and promotes primordial germ cell apoptosis.

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.

Differential expression and regulation by activin of the neurotrophins BDNF and NT4 during human and mouse ovarian development.

The tropomyosin-related kinase (Trk) B neurotrophin receptor is essential for ovarian germ cell survival and primordial follicle formation, but the contributions of its ligands, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4), are unknown. We have investigated their expression and regulation in developing human and mouse ovaries. BDNF expression increased with increasing gestation, expression of human NTF4 and of both Ntf5 and Bdnf in the mouse was unchanged.

Prostaglandin E2 as a regulator of germ cells during ovarian development.

Context: The formation of primordial follicles occurs during fetal life yet is critical to the determination of adult female fertility. Prior to this stage, germ cells proliferate, enter meiosis, and associate with somatic cells. Growth and survival factors implicated in these processes include activin A (INHBA), the neurotrophins BDNF and NT4 (NTF5), and MCL1.

Brain-derived neurotrophic factor is a regulator of human oocyte maturation and early embryo development.

Objective: To investigate a role for brain-derived neurotrophic factor (BDNF) in human oocyte maturation.

Design: Prospective study.

Setting: Research institute.

Activin signals via SMAD2/3 between germ and somatic cells in the human fetal ovary and regulates kit ligand expression.

Ovarian germ cell survival is dependent upon the formation of primordial follicles, which occurs during fetal life in the human. Activin contributes to germ cell proliferation and survival at this time. SMADs2 and 3 are central elements in the activin signalling pathway and thus indicate sites of activin action.

Molecular profiling of the human testis reveals stringent pathway-specific regulation of RNA expression following gonadotropin suppression and progestogen treatment.

Gonadotropin withdrawal induces changes in gene expression in all 3 major cell types of the testis. Knowledge of the genes affected, in both the presence and absence of additional progestogen, will give insight into the regulation of human testicular function and aid development of novel contraceptive methods. We have undertaken a whole-genome analysis of RNA expression in testicular biopsies from normal men and after 4 weeks of gonadotropin suppression induced by gonadotropin-releasing hormone antagonist plus testosterone administration sufficient to cause marked suppression of spermatogenesis.

Direct effect of progestogen on gene expression in the testis during gonadotropin withdrawal and early suppression of spermatogenesis.

Context: Testicular production of steroids and gametes is under gonadotropin support, but there is little information as to the molecular mechanisms by which these are regulated in the human. The testicular response to gonadotropin withdrawal is important for the development of effective contraceptive methods.

Objective: Our objective was investigation of expression of genes in the normal human testis reflecting steroidogenesis, Sertoli cell function, and spermatogenesis after short-term gonadotropin withdrawal and the effects of activating testicular progesterone receptors.

A mouse model of tuberous sclerosis 1 showing background specific early post-natal mortality and metastatic renal cell carcinoma.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in either the TSC1 or the TSC2 genes and characterized by the development of benign hamartomatous growths in multiple organ systems. We have inactivated Tsc1 in the mouse germ line by gene targeting in ES cells and confirmed that the mutant allele (Tsc1-) has a recessive embryonic lethal phenotype. We found that a significant number (approximately 27%) of heterozygous (Tsc1+/-) mice on the C57BL/6 background died before weaning (P = 0.

Increased expression of the FIGLA transcription factor is associated with primordial follicle formation in the human fetal ovary.

The process of primordial follicle formation is central to the determination of a woman's reproductive lifespan, and in humans occurs towards the end of mid-gestation. Gene knockout analysis in the mouse has shown that Figla, a transcription factor specifically expressed in germ cells, is essential for oocytes to survive and form primordial follicles. Our objective was to investigate whether a human homologue present in the genome database plays a similar role in human ovary development.

Identification of a novel missense mutation that is as damaging to DAX-1 repressor function as a nonsense mutation.

Mutations in the DAX-1 (NROB1) gene result in X-linked congenital adrenal hypoplasia (AHC) and hypogonadotropic hypogonadism. The clinical presentation is usually as adrenal insufficiency in early life, with hypogonadotropic hypogonadism detected at the time of expected puberty. In this study we identified mutations in the DAX-1 gene of two patients with AHC.