The GMs Positional Understanding Rar
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Sometimes the moves that seem most anti-positional are the most instructive. Paradox always provides an opportunity for reevaluation. Watch this idea in action in GM Gregory Kaidanov's newest video.
GM Mikhail Botvinnik: Botvinnik possessed an iron logic and a scientific method of preparation; however, unlike many positional players, Botvinnik was very principled and often went for risky systems.
Cellular competence, fate determination, and differentiation are influenced by the external signals cells receive. While these external signals can take the form of steroid hormones, protein growth factors, or other molecules, their presence is typically communicated by signal-responsive transcription factors (TFs). The effect of a signal on gene expression, and ultimately on cell fate, depends on where such TFs bind to the genome. Therefore, understanding how signal-responsive TFs are integrated into a dynamic cellular context will further our knowledge of the mechanisms guiding the acquisition of specific cellular identities.
We have described a compact transcriptional response to RA at the initiation of neurogenesis, which may be potentiated by associations between RAR and earlier regulatory events. As more regulatory data are collected from a greater diversity of cell types and developmental stages, it will be of interest to further elucidate temporal dependencies between the genomic occupancy of regulatory proteins. Indeed, exploring such temporal networks of binding events may lead to greater understanding of the influences on cell fate during differentiation.
Regulation of lineage specification and differentiation in embryonic stem (ES) cells can be achieved through the activation of endogenous signaling, an avenue for potential application in regenerative medicine. During vertebrate development, retinoic acid (RA) plays an important role in body axis elongation and mesoderm segmentation in that graded exposure to RA provides cells with positional identity and directs commitment to specific tissue lineages. Nevertheless, bexarotene, a clinically approved rexinoid, enhances the specification and differentiation of ES cells into skeletal myocytes more effectively than RA. Thus profiling the transcriptomes of ES cells differentiated with bexarotene or RA permits the identification of different genetic targets and signaling pathways that may contribute to the difference of bexarotene and RA in efficiency of myogenesis. Interestingly, bexarotene induces the early expression of a myogenic progenitor marker, Meox1, while the expression of many RA targets is also enhanced by bexarotene. Several signaling molecules involved in the progression of myogenic specification and commitment are differentially regulated by bexarotene and RA, suggesting that early targets of rexinoid allow the coordinated regulation of molecular events which leads to efficient myogenic differentiation in ES cells.
Abstract:We know little about the control of positional information (PI) during axolotl limb regeneration, which ensures that the limb regenerates exactly what was amputated, and the work reported here investigates this phenomenon. Retinoic acid administration changes the PI in a proximal direction so that a complete limb can be regenerated from a hand. Rather than identifying all the genes altered by RA treatment of the limb, we have eliminated many off-target effects by using retinoic acid receptor selective agonists. We firstly identify the receptor involved in this respecification process as RARα and secondly, identify the genes involved by RNA sequencing of the RARα-treated blastemal mesenchyme. We find 1177 upregulated genes and 1403 downregulated genes, which could be identified using the axolotl genome. These include several genes known to be involved in retinoic acid metabolism and in patterning. Since positional information is thought to be a property of the cell surface of blastemal cells when we examine our dataset with an emphasis on this aspect, we find the top canonical pathway is integrin signaling. In the extracellular matrix compartment, we find a MMP and several collagens are upregulated; several cell membrane genes and secretory factors are also upregulated. This provides data for future testing of the function of these candidates in the control of PI during limb regeneration.Keywords: retinoic acid; retinoic acid receptor; RARα; positional information; axolotl; limb regeneration
All-trans retinoic acid (ATRA) plays key roles in neurogenesis mediated by retinoic acid receptors (RARs). RARs are important targets for the therapeutic regulation of neurogenesis but effective drug development depends on modelling-based strategies to design high-specificity ligands in combination with good biological assays to discriminate between target-specificity and off-target effects. Using neuronal differentiation as a model, the aim of this study was to test the hypothesis that responses across different temporal scales and assay platforms can be used as comparable measures of retinoid activity. In biological assays based on cell phenotype or behaviour, two structurally similar synthetic retinoids, differing in RAR affinity and specificity, retained their relative activities across different temporal scales. In contrast, assays based on the transcriptional activation of specific genes in their normal genomic context were less concordant with biological assays. Gene-induction assays for retinoid activity as modulators of neurogenesis require careful interpretation in the light of variation in ligand-receptor affinity, receptor expression and gene function. A better characterization of neuronal phenotypes and their regulation by retinoids is badly needed as a framework for understanding how to regulate neuronal development.
In summary, specific gene-induction assays for novel retinoids require careful interpretation as measures for their potential as modulators of neurogenesis. Changes in cell phenotype or behaviour over different temporal scales may, superficially, be simpler to interpret; nevertheless, a much better understanding and characterization of neuronal phenotypes and their regulation is badly needed to provide a framework for understanding the wider value of synthetic retinoids for regulating neuronal development.
Vitamin A (retinol) is a critical micronutrient required for the control of stem cell functions, cell differentiation, and cell metabolism in many different cell types, both during embryogenesis and in the adult organism. However, we must obtain vitamin A from food sources. Thus, the uptake and metabolism of vitamin A by intestinal epithelial cells, the storage of vitamin A in the liver, and the metabolism of vitamin A in target cells to more biologically active metabolites, such as retinoic acid (RA) and 4-oxo-RA, must be precisely regulated. Here, I will discuss the enzymes that metabolize vitamin A to RA and the cytochrome P450 Cyp26 family of enzymes that further oxidize RA. Because much progress has been made in understanding the regulation of ALDH1a2 (RALDH2) actions in the intestine, one focus of this review is on the metabolism of vitamin A in intestinal epithelial cells and dendritic cells. Another focus is on recent data that 4-oxo-RA is a ligand required for the maintenance of hematopoietic stem cell dormancy and the important role of RARβ (RARB) in these stem cells. Despite this progress, many questions remain in this research area, which links vitamin A metabolism to nutrition, immune functions, developmental biology, and nuclear receptor pharmacology.
Dendritic cells (DCs) capture and present antigens to naive T-cells, generating antigen-specific immune responses. Here, we focus on the DCs in the intestine, where many advances in our understanding of the actions of ALDH1a2 on DC function have been elucidated. The intestinal immune system exhibits some differences from the systemic immune system. Cells in the intestinal tract are exposed to large numbers of antigens, many of which are from harmless substances, and Treg cells, a type of T-cell, are primarily responsible for immunosuppression in the intestine (Coombes & Maloy 2007). During homeostasis, a subtype of DCs, CD103+ DCs, assists in maintaining intestinal tolerance by migrating to mesenteric lymph nodes, the lymph nodes between layers of the mesentery, a membrane that attaches the intestine to the abdominal wall. There these intestinal DCs (i) induce the gut-homing receptors CCR9 and α4β7 on T and B-cells, (ii) promote the development of Foxp3+ regulatory T-cells, and (iii) promote IgA class switching in naïve B-cells (Johansson-Lindbom et al. 2005, Schulz et al. 2009) (Fig. 2). Notably, RA, produced in CD103+ DCs by transcriptional activation of ALDH1a2, plays a major role in regulating these processes (Iwata et al. 2004, Coombes et al. 2007, Hammerschmidt et al. 2011, Gyöngyösi et al. 2013, Sato et al. 2013). Furthermore, in the presence of RA, naive T-cells can no longer properly differentiate into T-helper 17 (Th17 cells). Additionally, T-cell production of interleukin-4 and interferon-γ, cytokines that block T-reg differentiation, is reduced by RA (Bettelli et al. 2006, Sun et al. 2007, Xiao et al. 2008). In aggregate, these effects of DCs that produce RA in the intestine influence the balance between Treg and Th17 cells, favoring Treg cells. Importantly, in contrast to this CD103+ subtype of DCs in the intestine, DCs in the spleen and lymph nodes draining the skin generally do not exhibit high ALDH1a2 expression (Molenaar et al. 2011, Villablanca et al. 2011). 59ce067264
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