Notch signaling regulates ovarian follicle formation and coordinates follicular growth.

Ovarian follicles form through a process in which somatic pregranulosa cells encapsulate individual germ cells from germ cell syncytia. Complementary expression of the Notch ligand, Jagged1, in germ cells and the Notch receptor, Notch2, in pregranulosa cells suggests a role for Notch signaling in mediating cellular interactions during follicle assembly. Using a Notch reporter mouse, we demonstrate that Notch signaling is active within somatic cells of the embryonic ovary, and these cells undergo dramatic reorganization during follicle histogenesis. This coincides with a significant increase in the expression of the ligands, Jagged1 and Jagged2; the receptor, Notch2; and the target genes, Hes1 and Hey2. Histological examination of ovaries from mice with conditional deletion of Jagged1 within germ cells (J1 knockout [J1KO]) or Notch2 within granulosa cells (N2 knockout [N2KO]) reveals changes in follicle dynamics, including perturbations in the primordial follicle pool and antral follicle development. J1KO and N2KO ovaries also contain multi-oocytic follicles, which represent a failure to resolve germ cell syncytia, and follicles with enlarged oocytes but lacking somatic cell growth, signifying a potential role of Notch signaling in follicle activation and the coordination of follicle development. We also observed decreased cell proliferation and increased apoptosis in the somatic cells of both conditional knockout lines. As a consequence of these defects, J1KO female mice are subfertile; however, N2KO female mice remain fertile. This study demonstrates important functions for Jagged1 and Notch2 in the resolution of germ cell syncytia and the coordination of somatic and germ cell growth within follicles of the mouse ovary.

Effects of estradiol on transcriptional profiles in atherosclerotic iliac arteries in ovariectomized cynomolgus macaques.

OBJECTIVE: This study aimed to assess the in vivo effects of estradiol treatment on arterial gene expression in atherosclerotic postmenopausal female monkeys. METHODS: Eight ovariectomized cynomolgus monkeys were fed atherogenic diets for 6.5 years. The left iliac artery was biopsied before randomization to the estradiol group (human equivalent dose of 1 mg/d, n = 4) or the vehicle group (n = 4) for 8 months. The right iliac artery was obtained at necropsy. Transcriptional profiles in pretreatment versus posttreatment iliac arteries were compared to assess the responses of atherosclerotic arteries to estradiol. RESULTS: Iliac artery plaque size did not differ between the estradiol group and the placebo group at baseline or during the treatment period. Nevertheless, estradiol treatment was associated with increased expression of 106 genes and decreased expression of 26 genes in the iliac arteries. Estradiol treatment increased the expression of extracellular matrix genes, including the α1 chain of type I collagen, the α2 chain of type VI collagen, and fibulin 2, suggestive of an increase in the proportion or phenotype of smooth muscles or fibroblasts in lesions. Also increased were components of the insulin-like growth factor pathway (insulin-like growth factor 1, insulin-like growth factor binding protein 4, and insulin-like growth factor binding protein 5) and the Wnt signaling pathway (secreted frizzled-related protein 2, secreted frizzled-related protein 4, low-density lipoprotein receptor-related protein 6, and Wnt1-inducible signaling pathway protein 2). CONCLUSIONS: Estradiol treatment of monkeys with established atherosclerosis affected iliac artery gene expression, suggesting changes in the cellular composition of lesions. Moreover, it is probable that the presence of atherosclerotic plaque affected the gene expression responses of arteries to estrogen.

Gene expression signatures differ with extent of atherosclerosis in monkey iliac artery.

OBJECTIVE: The aim of this study was to evaluate global gene expression patterns in the common iliac arteries of monkeys with a varied extent of atherosclerosis. METHODS: The left common iliac artery was removed from ovariectomized cynomolgus monkeys (n = 12) after 6.5 years of consuming a diet containing fat and cholesterol at levels comparable with those consumed in Western populations. Arterial gene expression was analyzed using DNA microarray and real-time reverse transcription-polymerase chain reaction. RESULTS: Significant differential expression of 986 genes was observed in iliac arteries containing moderate to large atherosclerotic plaques compared with normal/minimally affected reference group arteries. Atherosclerosis-associated genes included cytokines, chemokines, components of signal transduction pathways, and transcriptional activators and repressors, as well as other functional categories. Real-time reverse transcription-polymerase chain reaction confirmed a differential expression of genes chosen from a variety of functional categories. Specifically, the expression of genes for estrogen receptor-1, claudin 11, and brain heart protocadherin 7 was reduced, whereas the expression of genes for apolipoprotein E, growth differentiation factor 15, superoxide dismutase-2, SET domain bifurcated 2, phospholipase A2 group IIA, phospholipase A2 group VII, and ring finger protein 149 was increased in atherosclerotic arteries. CONCLUSIONS: The gene expression environment in arteries containing atherosclerotic plaques is profoundly different from that of relatively unaffected arteries and reflects the cellular and molecular complexity of atherosclerosis and associated arterial remodeling processes.

Regulation of cadherin expression in the chicken neural crest by the Wnt/ß-catenin signaling pathway.

In neural crest cell development, the expression of the cell adhesion proteins cadherin-7 and cadherin-11 commences after delamination of the neural crest cells from the neuroepithelium. The canonical Wnt signaling pathway is known to drive this delamination step and is a candidate for inducing expression of these cadherins at this time. This project was initiated to investigate the role of canonical Wnt signaling in the expression of cadherin-7 and cadherin-11 by treating neural crest cells with Wnt3a ligand. Expression of cadherin-11 was first confirmed in the neural crest cells for the chicken embryo. The changes in the expression level of cadherin-7 and -11 following the treatment with Wnt3a were studied using real-time RT-PCR and immunostaining. Statistically significant upregulation in the mRNA expression of cadherin-7 and cadherin-11 and in the amount of cadherin-7 and cadherin-11 protein found in cell-cell interfaces between neural crest cells was observed in response to Wnt, demonstrating that cadherin-7 and cadherin-11 expressed by the migrating neural crest cells can be regulated by the canonical Wnt pathway.

Management of endometriosis-associated pain.

Endometriosis, a common cause of morbidity in reproductive-age females, results in pelvic pain and infertility. Endometriosis-associated pain can be approached with surgical or medical therapies. Conservative surgery maintains reproductive organs and is effective in the treatment of endometriosis-associated pain. A more radical surgical approach of hysterectomy with bilateral salpingo-oophorectomy remains a mainstay of therapy for patients who have completed childbearing. Current medical therapies rely upon interruption of normal cyclic ovarian hormone production resulting in an environment not conducive to the growth of endometriosis. Genomics promises to further characterize endometriosis and tailor therapies based on a woman's symptoms and reproductive goals.