Receptor activator of NF-B ligand (RANKL) is a key regulator for mammary gland development during pregnancy. RANKL-deficient mice display impaired development of lobulo-alveolar mammary structures. Similar mammary gland defects have been reported in mice lacking Id2. Here we report that RANKL induces the proliferation of mammary epithelial cells via Id2. RANKL triggers marked nuclear translocation of Id2 in mammary epithelial cells. In vivo studies further demonstrated the defective nuclear translocation of Id2, but the normal expression of cyclin D1, in the mammary epithelial cells of rankl ؊/؊ mice. In vitro studies with nuclear localization sequence-tagged Id2 revealed that the nuclear localization of Id2 itself is critical for the downregulation of p21 promoter activity. Moreover, RANKL stimulation failed to induce cell growth and to downregulate p21 expression in Id2 ؊/؊ mammary epithelial cells. Our results indicate that the inhibitor of helix-loop-helix protein, Id2, is critical to control the proliferation of mammary epithelial cells in response to RANKL stimulation.Mammary gland development mostly occurs postnatally, by the actions of pregnancy hormones, and proceeds in distinct steps. At birth, the mammary anlage consists of a few rudimentary ducts that occupy a small portion of the mammary fat pad. Pronounced ductal outgrowth and branching commences at puberty. At the onset of pregnancy, increased ductal side branching and extensive epithelial cell proliferation occur, resulting in the formation of lobulo-alveolar structures and the differentiation of secretory epithelia (13,14,39). These differentiation steps are essential to form a lactating mammary gland in pregnancy.The TNF family molecule, receptor activator of NF-B ligand (RANKL; also known as OPGL, ODF, and TRANCE), is a key factor for osteoclast differentiation and/or activation and dendritic cell survival (1,20,41,42). RANKL-deficient mice exhibit severe osteopetrosis and tooth eruption failure due to a complete absence of osteoclasts (19). In addition to the regulation of bone remodeling and immune functions, we have previously shown that RANKL plays a critical role in mammary gland development during pregnancy. Mice lacking RANKL or its receptor, RANK, show impaired lobulo-alveolar development during pregnancy, owing to intrinsic defects in both the proliferation and survival of mammary gland epithelial cells (9). These mutant mice also display a complete transcriptional block in the -casein gene. The defect of -casein gene expression in RANKL-null mice is due to the failure of nuclear translocation of CCAAT/enhancer binding protein  (C/EBP) (18). These findings indicate that RANKL and RANK are essential for the development of a lactating mammary gland during pregnancy.In mammary glands, as well as osteoclasts and dendritic cells, RANKL-RANK interactions induce the phosphorylation and/or activation of IB kinase (IKK), a complex composed of IKK␣, IKK, and IKK␥/NEMO (6, 40). This phosphorylation event leads to polyubiquitination and prot...
Lin28, a well-known RNA-binding protein, regulates diverse cellular properties. All physiological functions of Lin28A characterized so far have been attributed to its repression of let-7 miRNA biogenesis or modulation of mRNA translational efficiency. Here we show that Lin28A directly binds to a consensus DNA sequence in vitro and in mouse embryonic stem cells in vivo. ChIP-seq and RNA-seq reveal enrichment of Lin28A binding around transcription start sites, and a positive correlation between its genomic occupancy and expression of many associated genes. Mechanistically, Lin28A recruits 5-methylcytosine-dioxygenase Tet1 to genomic binding sites to orchestrate 5-methylcytosine and 5-hydroxymethylcytosine dynamics. Either Lin28A or Tet1 knockdown leads to dysregulated DNA methylation and expression of common target genes. These results reveal a surprising role for Lin28A in transcriptional regulation via epigenetic DNA modifications and have implications for understanding mechanisms underlying versatile functions of Lin28A in mammalian systems.
Although terminal differentiation of intestinal epithelium is essential for the efficient digestion and absorption of nutrients, little is known about the molecular mechanisms underlying this process. Recent studies have shown that Elf3 (E74-like factor 3), a member of the ETS transcription factor family, has an essential role in the terminal differentiation of absorptive enterocytes and mucus-secreting goblet cells. Here, we demonstrated that Crif1 (CR6-interacting factor 1) functions as transcriptional coactivator of Elf3 in intestinal epithelium differentiation. The intestinal epithelium-specific Crif1-deficient mice died soon after birth and displayed severe alterations of tissue architecture in the small intestine, including poor microvillus formation and abnormal differentiation of absorptive enterocytes. Strikingly, these phenotypes are largely similar to that of Elf3-deficient mice, suggesting that Elf3 signaling in the intestinal epithelium depends on the Crif1 expression. We dissected this relationship further and found that Crif1 indeed interacted with Elf3 through its ETS DNA binding domain and enhanced the transcriptional activity of Elf3 by regulating the DNA binding activity. Knockdown of Crif1 by RNA interference conversely attenuated the transcriptional activity of Elf3. Consistently, the expression level of Tgf-RII (transforming growth factor  type II receptor), a critical target gene of Elf3, was dramatically reduced in the Crif1-deficient mice. Our results reveal that Crif1 is a novel and essential transcriptional coactivator of Elf3 for the terminal differentiation of absorptive enterocytes.
It is shown that the Berezinski-Kosterlitz-Thouless phase transition that has been found in D3-D5 brane systems with nonzero magnetic field and charge density can also be found by tuning an extra-dimensional magnetic flux. We find numerical solutions for the probe D5-brane embedding and discuss properties of the solutions. We also demonstrate that the nontrivial embeddings include those which can be regarded as spontaneously breaking chiral symmetry.
The possibility of inter-layer exciton condensation in a holographic D3-probe-D5 brane model of a strongly coupled double monolayer Dirac semi-metal in a magnetic field is studied in detail. It is found that, when the charge densities on the layers are exactly balanced so that, at weak coupling, the Fermi surfaces of electrons in one monolayer and holes in the other monolayer would be perfectly nested, inter-layer condensates can form for any separation of the layers. The case where both monolayers are charge neutral is special. There, the inter-layer condensate occurs only for small separations and is replaced by an intra-layer exciton condensate at larger separations. The phase diagram for charge balanced monolayers for a range layer separations and chemical potentials is found. We also show that, in semi-metals with multiple species of massless fermions, the balance of charges required for Fermi surface nesting can occur spontaneously by breaking some of the internal symmetry of the monolayers. This could have important consequences for experimental attempts to find inter-layer condensates.
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