Theca cells function in a diverse range of necessary roles during folliculogenesis; to synthesize androgens, provide crosstalk with granulosa cells and oocytes during development, and provide structural support of the growing follicle as it progresses through the developmental stages to produce a mature and fertilizable oocyte. Thecal cells are thought to be recruited from surrounding stromal tissue by factors secreted from an activated primary follicle. The precise origin and identity of these recruiting factors are currently not clear, but it appears that thecal recruitment and/or differentiation involves not just one signal, but a complex and tightly controlled combination of multiple factors. It is clear that thecal cells are fundamental for follicular growth, providing all the androgens required by the developing follicle(s) for conversion into estrogens by the granulosa cells. Their function is enabled through the establishment of a vascular system providing communication with the pituitary axis throughout the reproductive cycle, and delivering essential nutrients to these highly active cells. During development, the majority of follicles undergo atresia, and the theca cells are often the final follicular cell type to die. For those follicles that do ovulate, the theca cells then undergo hormone-dependent differentiation into luteinized thecal cells of the corpus luteum. While the theca is an essential component of follicle development and ovulation, we do not yet fully understand the control of recruitment and function of theca cells, an important consideration since their function appears to be altered in certain causes of infertility.
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer among men in the developed world. There is a need, for both clinical and scientific reasons, to find markers to identify patients with aggressive disease as early as possible, and to understand the events leading to malignant transformation and susceptibility to metastasis. We report the first largescale gene expression analysis of a unique HNSCC location, the hypopharynx. Four normal and 34 tumour samples were analysed with 12 600 gene microarrays. Clusters of differentially expressed genes were identified in the chromosomal regions 3q27.3, 17q21.2-q21.31, 7q11.22-q22.1 and 11q13.1-q13.3, which, interestingly, have already been identified by comparative genomic hybridization (CGH) as major regions of gene amplification. We showed that six overexpressed genes (EIF4G1, DVL3, EPHB4, MCM7, BRMS1 and SART1) located in these regions are indeed amplified. We report 119 genes that are highly differentially expressed between 'early' tumours and normal samples. Of these, we validated by quantitative PCR six novel poorly characterized genes. These genes are potential new markers of HNSCC. Comparing patients with relatively nonaggressive and aggressive tumours (without or with clinical evidence of metastasis 3 years after surgery), we identified 164 differentially expressed genes potentially involved in the acquisition of metastatic potential. This study contributes to the understanding of HNSCC, staging patients into prognostic groups and identifying high-risk patients who may benefit from more aggressive treatment.
Genetic mechanisms underlying abnormal early neural development in toddlers with Autism Spectrum Disorder (ASD) remain uncertain due to the impossibility of direct brain gene expression measurement during critical periods of early development. Recent findings from a multi‐tissue study demonstrated high expression of many of the same gene networks between blood and brain tissues, in particular with cell cycle functions. We explored relationships between blood gene expression and total brain volume (TBV) in 142 ASD and control male toddlers. In control toddlers, TBV variation significantly correlated with cell cycle and protein folding gene networks, potentially impacting neuron number and synapse development. In ASD toddlers, their correlations with brain size were lost as a result of considerable changes in network organization, while cell adhesion gene networks significantly correlated with TBV variation. Cell cycle networks detected in blood are highly preserved in the human brain and are upregulated during prenatal states of development. Overall, alterations were more pronounced in bigger brains. We identified 23 candidate genes for brain maldevelopment linked to 32 genes frequently mutated in ASD. The integrated network includes genes that are dysregulated in leukocyte and/or postmortem brain tissue of ASD subjects and belong to signaling pathways regulating cell cycle G1/S and G2/M phase transition. Finally, analyses of the CHD8 subnetwork and altered transcript levels from an independent study of CHD8 suppression further confirmed the central role of genes regulating neurogenesis and cell adhesion processes in ASD brain maldevelopment.
Head and neck squamous cell carcinoma (HNSCC) is common worldwide and is associated with a poor rate of survival. Identification of new markers and therapeutic targets, and understanding the complex transformation process, will require a comprehensive description of genome expression, that can only be achieved by combining different methodologies. We report here the HNSCC transcriptome that was determined by exhaustive differential display (DD) analysis coupled with validation by different methods on the same patient samples. The resulting 820 nonredundant sequences were analysed by high throughput bioinformatics analysis. Human proteins were identified for 73% (596) of the DD sequences. A large proportion (>50%) of the remaining unassigned sequences match ESTs (expressed sequence tags) from human tumours. For the functionally annotated proteins, there is significant enrichment for relevant biological processes, including cell motility, protein biosynthesis, stress and immune responses, cell death, cell cycle, cell proliferation and/or maintenance and transport. Three of the novel proteins (TMEM16A, PHLDB2 and ARH-GAP21) were analysed further to show that they have the potential to be developed as therapeutic targets.
The mouse genome possesses five genes encoding proteins homologous to human Leu-13. The Leu-13 protein associates with immune cell receptor activation complexes: a monoclonal antibody against Leu-13 induces T and B cells to form homotypic aggregates, inhibits activation-induced proliferation and induces the shedding of L-selectin. The mouse fragilis proteins have not been previously analyzed as components of the immune response. Antibody and nucleic acid reagents were generated that are specific for each of the five fragilis gene products. Expression of some of these genes (fragilis and fragilis3) is wide spread in a variety of mouse immune (and nonimmune) tissues while others (fragilis5) appear to be much more restricted. These proteins have been predicted to span the membrane twice with both amino-and carboxyl-terminal sequences extracellular: we show that a highly conserved loop of the protein between the transmembrane domains is intracellular. The fragilis proteins are associated with tetraspanin proteins CD81 and CD9: B cell activation positions fragilis into lipid rafts along with the CD81, CD19, and CD21. The mouse functional equivalent to human Leu-13 may not be single gene product, but instead may require the contribution of multiple fragilis proteins.
Despite antibiotic treatment, up to 40% of patients have impaired fertility after epididymitis due to serovars of Escherichia coli, a frequent pathogen. The reasons for infertility are unclear, but it may result from epididymal duct obstruction. To determine whether E. coli infection of the epididymis causes obstruction due to fibrosis, and to identify the key mediators, tissues from patients with epididymitis were assessed. Additionally, epididymitis was induced with uropathogenic E. coli (UPEC) or commensal serovars in wild-type and MyD88(-/-) mice, which are relatively unresponsive to bacterial pathogens. Epididymal organ cultures were treated with activin A and bacteria and their histology and levels of cytokines and fibrosis markers were analysed. Patients with epididymitis showed severe fibrosis of the epididymal duct. In mice, UPEC infection also caused fibrosis and ductal obstruction in the cauda epididymis. Levels of mRNA for fibrotic markers (α-smooth muscle actin, fibronectin) and cytokines (activin A, TNFα, IL-1α, IL-1β, IL-6) and total collagen levels were significantly elevated. This fibrotic response was blunted by the loss of MyD88. Activin A induced fibrosis in cultured epididymis, which was inhibited by the activin-binding protein follistatin. In summary, bacterial epididymitis causes fibrosis and obstruction. The milder tissue damage in Myd88(-/-) UPEC epididymitis highlights the importance of the host response to infection in causing epididymal damage. Elevated levels of activin A in vivo and fibrotic remodelling elicited by activin A in vitro indicate that this cytokine is a potential target for supplementary treatment to antibiotic therapy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The importance of Wnt signaling for postnatal testis function has been previously studied in several mouse models, with chronic pathway disruption addressing its function in Sertoli cells and in postmeiotic germ cells. While chronic beta-catenin deletion in Sertoli cells does not profoundly affect testis development, new data indicate that Wnt signaling is required at multiple stages of spermatogenesis. We used two mouse models that allow acute disruption of Wnt signaling to explore the importance of regulated Wnt pathway activity for normal germ cell development in adult male mice. Short-term induction of mutations in Adenomatous polyposis coli (Apc) and beta-catenin (Ctnnbl), which increase and decrease Wnt signaling levels, were generated in AhCre Apc(fl/fl) and AhCre Ctnnb1(fl/fl) mice, respectively. Each exhibited a distinct phenotype of disrupted spermatogenesis that was evident within 24 h and persisted for up to 4 days. Outcomes included germ cell apoptosis and rapid loss and altered blood-testis barrier protein distribution and morphology. The functional significance of nuclear localized beta-catenin protein in spermatocytes and round spermatids, indicative of active Wnt signaling, was highlighted by the profound loss of postmitotic germ cells in both models. Developmentally regulated Wnt signaling mediators identified through transcriptional profiling of wild-type and AhCre Ctnnb1(fl/fl) mouse testes identified Wnt receptors (e.g., Fzd4) and ligands (e.g., Wnt3, Wnt3a, Wnt5b, Wnt7a, and Wnt8b). This demonstration that Wnt signaling control is essential for adult spermatogenesis supports the growing understanding that its disruption may underpin certain cases of male infertility.
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