A noncoding RNA is a potential marker of cell fate during mammary gland development.
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ABSTRACT:
SUBMITTER: Ginger MR
PROVIDER: S-EPMC1420634 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveWater buffalo, an important domestic animal in tropical and subtropical regions, play an important role in agricultural economy. It is an important source for milk, meat, horns, skin, and draft power, especially its rich milk that is the great source of cream, butter, yogurt, and many cheeses. In recent years, long noncoding RNAs (lncRNAs) have been reported to play pivotal roles in many biological processes. Previous studies for the mammary gland development of water buffalo mainly focus on protein coding genes. However, lncRNAs of water buffalo remain poorly understood, and the regulation relationship between mammary gland development/milk production traits and lncRNA expression is also unclear.MethodsHere, we sequenced 22 samples of the milk somatic cells from three lactation stages and integrated the current annotation and identified 7,962 lncRNA genes.ResultsBy comparing the lncRNA genes of the water buffalo in the early, peak, and late different lactation stages, we found that lncRNA gene lnc-bbug14207 displayed significantly different expression between early and late lactation stages. And lnc-bbug14207 may regulate neighboring milk fat globule-EGF factor 8 (MFG-E8) and hyaluronan and proteoglycan link protein 3 (HAPLN3) protein coding genes, which are vital for mammary gland development.ConclusionThis study provides the first genome-wide identification of water buffalo lncRNAs and unveils the potential lncRNAs that impact mammary gland development.
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Project description:The hierarchical relationships between stem cells and progenitors that guide mammary gland morphogenesis are still poorly defined. While multipotent basal stem cells have been found within the myoepithelial compartment, the in vivo lineage potential of luminal progenitors is unclear. Here we used the expression of the Notch1 receptor, previously implicated in mammary gland development and tumorigenesis, to elucidate the hierarchical organization of mammary stem/progenitor cells by lineage tracing. We found that Notch1 expression identifies multipotent stem cells in the embryonic mammary bud, which progressively restrict their lineage potential during mammary ductal morphogenesis to exclusively generate an ERαneg luminal lineage postnatally. Importantly, our results show that Notch1-labelled cells represent the alveolar progenitors that expand during pregnancy and survive multiple successive involutions. This study reveals that postnatal luminal epithelial cells derive from distinct self-sustained lineages that may represent the cells of origin of different breast cancer subtypes.
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Project description:The steroid hormone, 17β-estradiol (E2), plays critical role in various cellular processes such as cell proliferation, differentiation, migration and apoptosis, and is essential for reproduction and mammary gland development. E2 actions are mediated by two classical nuclear hormone receptors, estrogen receptor α and β (ERs). The activity of ERs depends on the coordinated activity of ligand binding, post-translational modifications (PTMs), and importantly the interaction with their partner proteins called "coregulators." Because coregulators are proved to be crucial for ER transcriptional activity, and majority of breast cancers are ERα positive, an increased interest in the field has led to the identification of a large number of coregulators. In the last decade, gene knockout studies using mouse models provided impetus to our further understanding of the role of these coregulators in mammary gland development. Several coregulators appear to be critical for terminal end bud (TEB) formation, ductal branching and alveologenesis during mammary gland development. The emerging studies support that, coregulators along with the other ER partner proteins called "pioneer factors" together contribute significantly to E2 signaling and mammary cell fate. This review discusses emerging themes in coregulator and pioneer factor mediated action on ER functions, in particular their role in mammary gland cell fate and development.
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Project description:BackgroundThe Neuregulin family of ligands and their receptors, the Erbb tyrosine kinases, have important roles in epidermal and mammary gland development as well as during carcinogenesis. Previously, we demonstrated that Neuregulin3 (Nrg3) is a specification signal for mammary placode formation in mice. Nrg3 is a growth factor, which binds and activates Erbb4, a receptor tyrosine kinase that regulates cell proliferation and differentiation. To understand the role of Neuregulin3 in epidermal morphogenesis, we have developed a transgenic mouse model that expresses Nrg3 throughout the basal layer (progenitor/stem cell compartment) of mouse epidermis and the outer root sheath of developing hair follicles.ResultsTransgenic females formed supernumerary nipples and mammary glands along and adjacent to the mammary line providing strong evidence that Nrg3 has a role in the initiation of mammary placodes along the body axis. In addition, alterations in morphogenesis and differentiation of other epidermal appendages were observed, including the hair follicles. The transgenic epidermis is hyperplastic with excessive sebaceous differentiation and shows striking similarities to mouse models in which c-Myc is activated in the basal layer including decreased expression levels of the adhesion receptors, alpha6-integrin and beta1-integrin.ConclusionThese results indicate that the epidermis is sensitive to Nrg3 signaling, and that this growth factor can regulate cell fate of pluripotent epidermal cell populations including that of the mammary gland. Nrg3 appears to act, in part, by inducing c-Myc, altering the proliferation and adhesion properties of the basal epidermis, and may promote exit from the stem cell compartment. The results we describe provide significant insight into how growth factors, such as Nrg3, regulate epidermal homeostasis by influencing the balance between stem cell renewal, lineage selection and differentiation.
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Project description:Bone marrow mesenchymal stem cells (BMSCs) exhibit an age-related lineage switch between osteogenic and adipogenic fates, which contributes to bone loss and adiposity. Here we identified a long noncoding RNA, Bmncr, which regulated the fate of BMSCs during aging. Mice depleted of Bmncr (Bmncr-KO) showed decreased bone mass and increased bone marrow adiposity, whereas transgenic overexpression of Bmncr (Bmncr-Tg) alleviated bone loss and bone marrow fat accumulation. Bmncr regulated the osteogenic niche of BMSCs by maintaining extracellular matrix protein fibromodulin (FMOD) and activation of the BMP2 pathway. Bmncr affected local 3D chromatin structure and transcription of Fmod. The absence of Fmod modified the bone phenotype of Bmncr-Tg mice. Further analysis revealed that Bmncr would serve as a scaffold to facilitate the interaction of TAZ and ABL, and thus facilitate the assembly of the TAZ and RUNX2/PPARG transcriptional complex, promoting osteogenesis and inhibiting adipogenesis. Adeno-associated viral-mediated overexpression of Taz in osteoprogenitors alleviated bone loss and marrow fat accumulation in Bmncr-KO mice. Furthermore, restoring BMNCR levels in human BMSCs reversed the age-related switch between osteoblast and adipocyte differentiation. Our findings indicate that Bmncr is a key regulator of the age-related osteogenic niche alteration and cell fate switch of BMSCs.
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Project description:The cycling properties of mammary stem and progenitor cells is not well understood. To determine the division properties of these cells, we administered synthetic nucleosides for varying periods of time to mice at different stages of postnatal development and monitored the rate of uptake of these nucleosides in the different mammary cell compartments. Here we show that most cell division in the adult virgin gland is restricted to the oestrogen receptor-expressing luminal cell lineage. Our data also demonstrate that the oestrogen receptor-expressing, milk and basal cell subpopulations have telomere lengths and cell division kinetics that are not compatible with these cells being hierarchically organized; instead, our data indicate that in the adult homeostatic gland, each cell type is largely maintained by its own restricted progenitors. We also observe that transplantable stem cells are largely quiescent during oestrus, but are cycling during dioestrus when progesterone levels are high.
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Project description:The transcription factor E74-like factor 5 (Elf5) functions downstream of the prolactin receptor signaling pathway and plays an important role in mammary gland development. Using conditional mouse knockouts, we have previously shown that Elf5-null mammary glands exhibit a complete failure of alveologenesis during pregnancy. The Elf5-null developmental phenotype is mediated through alteration in the expression of several critical genes involved in alveologenesis, particularly those belonging to the JAK/STAT pathway. Here, we demonstrate that in addition to regulating terminal differentiation of alveolar cells, Elf5 also plays a critical role in determining cell fate and in regulating the stem/progenitor function of the mammary epithelium. Targeted deletion of Elf5 in the mammary glands leads to accumulation of cell types with dual luminal/basal properties such as coexpression of K8 and K14 and an increase in CD61(+) luminal progenitor population during pregnancy. Further interrogation suggests that the abnormal increase in K14(+) K8(+) cells may represent the CD61(+) luminal progenitors blocked in differentiation. Remarkably, Elf5 deficiency in mammary epithelium also triggers an increase of adult mammary stem activity as evidenced by the accumulation of mammary stem cell (MaSC)-enriched cell population in both pregnant and virgin mice and further confirmed by mammosphere and transplantation assays. Additional support for this phenotype comes from the enriched MaSC gene signature based on transcriptomic analysis of the Elf5-null mammary gland. Finally, our biochemical studies suggest that Elf5 loss leads to hyperactivation of the Notch signaling pathway, which might constitute in part, the underlying molecular mechanism for the altered cell lineage decisions in Elf5-null mammary epithelial cells.
| S-EPMC5606133 | biostudies-literature
Project description:During mammary gland development, an epithelial bud undergoes branching morphogenesis to expand into a continuous tree-like network of branched ducts [1]. The process involves multiple cell types that are coordinated by hormones and growth factors coupled with signaling events including Wnt and Hedgehog [2-5]. Primary cilia play key roles in the development of many organs by coordinating extracellular signaling (of Wnt and Hedgehog) with cellular physiology [6-8]. During mammary development, we find cilia on luminal epithelial, myoepithelial, and stromal cells during early branching morphogenesis when epithelial ducts extend into the fat pad and undergo branching morphogenesis. When branching is complete, cilia disappear from luminal epithelial cells but remain on myoepithelial and stromal cells. Ciliary dysfunction caused by intraflagellar transport defects results in branching defects. These include decreased ductal extension and decreased secondary and tertiary branching, along with reduced lobular-alveolar development during pregnancy and lactation. We find increased canonical Wnt and decreased Hedgehog signaling in the mutant glands, which is consistent with the role of cilia in regulating these pathways [6-11]. In mammary gland and other organs, increased canonical Wnt [12-14] and decreased Hedgehog [15, 16] signaling decrease branching morphogenesis, suggesting that Wnt and Hedgehog signaling connect ciliary dysfunction to branching defects.
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Project description:Long noncoding RNAs (lncRNAs) have emerged as important regulators of diverse cellular processes, but their roles in the developing immune system are poorly understood. In this study, we analysed lncRNA expression during human B-cell development by array-based expression profiling of eleven distinct flow-sorted B-cell subsets, comprising pre-B1, pre-B2, immature, naive, memory, and plasma cells from bone marrow biopsies (n = 7), and naive, centroblast, centrocyte, memory, and plasmablast cells from tonsil tissue samples (n = 6), respectively. A remapping strategy was used to assign the array probes to 37630 gene-level probe sets, reflecting recent updates in genomic and transcriptomic databases, which enabled expression profiling of 19579 long noncoding RNAs, comprising 3947 antisense RNAs, 5277 lincRNAs, 7625 pseudogenes, and 2730 additional lncRNAs. As a first step towards inferring the functions of the identified lncRNAs in developing B-cells, we analysed their co-expression with well-characterized protein-coding genes, a method known as "guilt by association". By using weighted gene co-expression network analysis, we identified 272 lincRNAs, 471 antisense RNAs, 376 pseudogene RNAs, and 64 lncRNAs within seven sub-networks associated with distinct stages of B-cell development, such as early B-cell development, B-cell proliferation, affinity maturation of antibody, and terminal differentiation. These data provide an important resource for future studies on the functions of lncRNAs in development of the adaptive immune response, and the pathogenesis of B-cell malignancies that originate from distinct B-cell subpopulations.
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Project description:Acquisition of cis-elements is a major driving force for rewiring a gene regulatory network. Several kinds of transposable elements (TEs), mostly retrotransposons that propagate via a copy-and-paste mechanism, are known to possess transcription factor binding motifs and have provided source sequences for enhancers/promoters. However, it remains largely unknown whether retrotransposons have spread the binding sites of master regulators of morphogenesis and accelerated cis-regulatory expansion involved in common mammalian morphological features during evolution. Here, I demonstrate that thousands of binding sites for estrogen receptor α (ERα) and three related pioneer factors (FoxA1, GATA3 and AP2γ) that are essential regulators of mammary gland development arose from a spreading of the binding motifs by retrotransposons. The TE-derived functional elements serve primarily as distal enhancers and are enriched around genes associated with mammary gland morphogenesis. The source TEs occurred via a two-phased expansion consisting of mainly L2/MIR in a eutherian ancestor and endogenous retrovirus 1 (ERV1) in simian primates and murines. Thus the build-up of potential sources for cis-elements by retrotransposons followed by their frequent utilization by the host (co-option/exaptation) may have a general accelerating effect on both establishing and diversifying a gene regulatory network, leading to morphological innovation.
| S-EPMC7145552 | biostudies-literature