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The TET enzymes catalyze conversion of 5-methyl cytosine (5mC) to 5-hydroxymethyl cytosine (5hmC) and play important roles during development. TET1 has been particularly well-studied in pluripotent stem cells, but -KO mice are viable, and the most marked defect is abnormal ovarian follicle development, resulting in impaired fertility. We hypothesized that TET1 might play a role in the central control of reproduction by regulating expression of the gonadotropin hormones, which are responsible for follicle development and maturation and ovarian function. We find that all three TET enzymes are expressed in gonadotrope-precursor cells, but mRNA levels decrease markedly with completion of cell differentiation, corresponding with an increase in expression of the luteinizing hormone gene, We demonstrate that poorly differentiated gonadotropes express a TET1 isoform lacking the N-terminal CXXC-domain, which represses gene expression directly and does not catalyze 5hmC at the gene promoter. We show that this isoform is also expressed in other differentiated tissues, and that it is regulated by an alternative promoter whose activity is repressed by the liganded estrogen and androgen receptors, and by the hypothalamic gonadotropin-releasing hormone through activation of PKA. Its expression is also regulated by DNA methylation, including at an upstream enhancer that is protected by TET2, to allow expression. The down-regulation of TET1 relieves its repression of the methylated gene promoter, which is then hydroxymethylated and activated by TET2 for full reproductive competence.

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Gonadotropes in the anterior pituitary gland are of particular importance within the hypothalamic-pituitary-gonadal axis because they provide a means of communication and thus a functional link between the brain and the gonads. Recent results indicate that female gonadotropes may be organized in the form of a network that shows plasticity and adapts to the altered endocrine conditions of different physiological states. However, little is known about functional changes on the molecular level within gonadotropes during these different conditions. In this study we capitalize on a binary genetic strategy in order to fluorescently label murine gonadotrope cells. Using this mouse model allows to produce an enriched gonadotrope population using fluorescence activated cell sorting to perform mRNA sequencing. By using this strategy, we analyze and compare the expression profile of murine gonadotropes in different genders and developmental and hormonal stages. We find that gonadotropes taken from juvenile males and females, from cycling females at diestrus and at proestrus, from lactating females, and from adult males each have unique gene expression patterns with approximately 100 to approximately 500 genes expressed only in one particular stage. We also demonstrate extensive gene-expression profile changes with up to approximately 2200 differentially expressed genes when comparing female and male development, juveniles and adults, and cycling females. Differentially expressed genes were significantly enriched in the GnRH signaling, calcium signaling, and MAPK signaling pathways by Kyoto Encyclopedia of Genes and Genomes analysis. Our data provide an unprecedented molecular view of the primary gonadotropes and reveal a high degree of molecular plasticity within the gonadotrope population.

As the main load-bearing structure in the human body, bone and cartilage are susceptible to damage in sports and other activities. The repair and regeneration of bone and articular cartilage have been extensively studied in the past decades. Traditional approaches have been widely applied in clinical practice, but the effect varies from person to person and may cause side effects. With the rapid development of tissue engineering and regenerative medicine, various biomaterials show great potential in the regeneration of bone and cartilage. Carbonbased nanomaterials are solid materials with different structures and properties composed of allotropes of carbon, which are classified into zero-, one-, and two-dimensional ones. This Review systemically summarizes the different types of carbon-based nanomaterials, including zero-dimensional (fullerene, carbon dots, nanodiamonds), one-dimensional (carbon nanotubes), and two-dimensional (graphenic materials) as well as their applications in bone, cartilage, and osteochondral regeneration. Current limitations and future perspectives of carbon-based nanomaterials are also discussed.