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Developmental Neurobiology Jan 2022The fate of neurons in the developing brain is largely determined by the combination of transcription factors they express. In particular, stem cells must follow...
The fate of neurons in the developing brain is largely determined by the combination of transcription factors they express. In particular, stem cells must follow different transcriptional cascades during differentiation in order to generate neurons with different neurotransmitter properties, such as glutamatergic and GABAergic neurons. In the mouse cerebral cortex, it has been shown that large Maf family proteins, MafA, MafB and c-Maf, regulate the development of specific types of GABAergic interneurons but are not expressed in glutamatergic neurons. In this study, we examined the expression of large Maf family proteins in the developing mouse olfactory bulb (OB) by immunohistochemistry and found that the cell populations expressing MafA and MafB are almost identical, and most of them express Tbr2. As Tbr2 is expressed in glutamatergic neurons in the OB, we further examined the expression of glutamatergic and GABAergic neuronal markers in MafA and MafB positive cells. The results showed that in the OB, MafA and MafB are expressed exclusively in glutamatergic neurons, but not in GABAergic neurons. We also found that few cells express c-Maf in the OB. These results indicate that, unlike the cerebral cortex, MafA and/or MafB may regulate the development of glutamatergic neurons in the developing OB. This study advances our knowledge about the development of glutamatergic neurons in the olfactory bulb, and also might suggest that mechanisms for the generation of projection neurons and interneurons differ between the cortex and the olfactory bulb, even though they both develop from the telencephalon.
Topics: Animals; Cell Differentiation; Interneurons; Mice; Neurons; Olfactory Bulb; Proto-Oncogene Proteins c-maf; Transcription Factors
PubMed: 34679244
DOI: 10.1002/dneu.22859 -
Developmental Cell Mar 2015Progenitor differentiation requires remodeling of genomic expression; however, in many tissues, such as epidermis, the spectrum of remodeled genes and the transcription...
Progenitor differentiation requires remodeling of genomic expression; however, in many tissues, such as epidermis, the spectrum of remodeled genes and the transcription factors (TFs) that control them are not fully defined. We performed kinetic transcriptome analysis during regeneration of differentiated epidermis and identified gene sets enriched in progenitors (594 genes), in early (159 genes), and in late differentiation (387 genes). Module mapping of 1,046 TFs identified MAF and MAFB as necessary and sufficient for progenitor differentiation. MAF:MAFB regulated 393 genes altered in this setting. Integrative analysis identified ANCR and TINCR lncRNAs as essential upstream MAF:MAFB regulators. ChIP-seq analysis demonstrated MAF:MAFB binding to known epidermal differentiation TF genes whose expression they controlled, including GRHL3, ZNF750, KLF4, and PRDM1. Each of these TFs rescued expression of specific MAF:MAFB target gene subsets in the setting of MAF:MAFB loss, indicating they act downstream of MAF:MAFB. A lncRNA-TF network is thus essential for epidermal differentiation.
Topics: Animals; Cell Differentiation; DNA-Binding Proteins; Epidermal Cells; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Gene Transfer Techniques; Humans; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; MafB Transcription Factor; Mice; Mice, Inbred NOD; Mice, SCID; Organogenesis; Positive Regulatory Domain I-Binding Factor 1; Proto-Oncogene Proteins c-maf; RNA Interference; RNA, Long Noncoding; RNA, Small Interfering; Repressor Proteins; Transcription Factors; Tumor Suppressor Proteins
PubMed: 25805135
DOI: 10.1016/j.devcel.2015.01.028 -
Biochemical and Biophysical Research... Apr 2016The large Maf transcription factors c-Maf and MafB are expressed in macrophage-lineage hematopoietic cells, but the expression patterns of MafB and c-Maf in macrophage...
The large Maf transcription factors c-Maf and MafB are expressed in macrophage-lineage hematopoietic cells, but the expression patterns of MafB and c-Maf in macrophage subtypes and tissue-resident macrophages have not been fully analyzed. First, we analyzed MafB and c-Maf protein expression in tissue-resident macrophages. Mouse lymph nodes, spleens, lungs, and kidneys were subjected to immunohistochemistry using anti-MafB and anti-c-Maf. Both MafB and c-Maf signals were observed in lymph node macrophages. In the splenic macrophages the MafB signal was detected by anti-MafB, but the c-Maf signal was not detected. No expression of c-Maf or MafB was detected in macrophages in the lung and kidney. Flow cytometry analysis revealed a similar pattern of GFP expression in Mafb/GFP knock-in heterozygous mice. To analyze these different expression patterns in greater detail, we examined the expression of MafB and c-Maf by quantitative RT-PCR in different cytokine- or LPS-induced macrophages in vitro. MafB expression was induced by IL-10 or IL-4 with IL-13 and was reduced by LPS or GM-CSF. By contrast, c-Maf expression was induced by IL-10 and reduced by IL-4 with IL-13 or GM-CSF. These results indicate that MafB and c-Maf have different expression patterns in macrophages, suggesting differences in function.
Topics: Animals; Bronchoalveolar Lavage; Cell Separation; Flow Cytometry; Gene Expression Regulation; Granulocyte-Macrophage Colony-Stimulating Factor; Green Fluorescent Proteins; Heterozygote; Interleukin-10; Interleukin-13; Interleukin-4; Kidney; Lipopolysaccharides; Lung; Macrophages; MafB Transcription Factor; Mice; Mice, Inbred C57BL; Mice, Transgenic; Proto-Oncogene Proteins c-maf; Real-Time Polymerase Chain Reaction; Signal Transduction; Tissue Distribution
PubMed: 26996125
DOI: 10.1016/j.bbrc.2016.03.063 -
ELife May 2020() and transcription factors (TFs) have compensatory roles in repressing somatostatin (SST) interneuron (IN) production in medial ganglionic eminence (MGE) secondary...
() and transcription factors (TFs) have compensatory roles in repressing somatostatin (SST) interneuron (IN) production in medial ganglionic eminence (MGE) secondary progenitors in mice. and conditional deletion (cDKO) decreases the survival of MGE-derived cortical interneurons (CINs) and changes their physiological properties. Herein, we show that (1) and are positively regulated by and to drive IN morphological maturation; (2) and promote expression which specifies parvalbumin (PV) INs; (3) , and are candidate markers of immature PV hippocampal INs (HIN). Furthermore, / neonatal cDKOs have decreased CINs and increased HINs, that express , an HIN specific marker. Our findings not only elucidate key gene targets of and that control IN development, but also identify for the first time TFs that differentially regulate CIN vs. HIN production.
Topics: Animals; Female; Gene Expression Regulation; Interneurons; MEF2 Transcription Factors; MafB Transcription Factor; Mice; Nervous System Diseases; Pregnancy; Protein Precursors; Proto-Oncogene Proteins c-maf; Receptors, CXCR4; Receptors, Opioid; Single-Cell Analysis; Synaptosomal-Associated Protein 25; Transcriptome
PubMed: 32452758
DOI: 10.7554/eLife.54903 -
Frontiers in Immunology 2020Defective IFN production and exacerbated inflammatory and pro-fibrotic responses are hallmarks of SARS-CoV-2 infection in severe COVID-19. Based on these hallmarks, and...
Defective IFN production and exacerbated inflammatory and pro-fibrotic responses are hallmarks of SARS-CoV-2 infection in severe COVID-19. Based on these hallmarks, and considering the pivotal role of macrophages in COVID-19 pathogenesis, we hypothesize that the transcription factors MAFB and MAF critically contribute to COVID-19 progression by shaping the response of macrophages to SARS-CoV-2. Our proposal stems from the recent identification of pathogenic lung macrophage subsets in severe COVID-19, and takes into consideration the previously reported ability of MAFB to dampen IFN type I production, as well as the critical role of MAFB and MAF in the acquisition and maintenance of the transcriptional signature of M-CSF-conditioned human macrophages. Solid evidences are presented that link overexpression of MAFB and silencing of MAF expression with clinical and biological features of severe COVID-19. As a whole, we propose that a high MAFB/MAF expression ratio in lung macrophages could serve as an accurate diagnostic tool for COVID-19 progression. Indeed, reversing the macrophage MAFB/MAF expression ratio might impair the exacerbated inflammatory and profibrotic responses, and restore the defective IFN type I production, thus becoming a potential strategy to limit severity of COVID-19.
Topics: COVID-19; Gene Expression Profiling; Gene Expression Regulation; Host-Pathogen Interactions; Humans; Macrophages; Maf Transcription Factors; MafB Transcription Factor; SARS-CoV-2; Severity of Illness Index
PubMed: 33312178
DOI: 10.3389/fimmu.2020.603507 -
Oncogene Aug 2002Anti-oxidant response element (ARE) and nuclear factors including Nrf2 and small Maf (MafG and MafK) proteins are known to regulate expression and induction of...
Anti-oxidant response element (ARE) and nuclear factors including Nrf2 and small Maf (MafG and MafK) proteins are known to regulate expression and induction of detoxifying enzyme genes including quinone oxidoreductase1 (NQO1). Nrf2 upregulates and small Maf proteins lacking the transcriptional activation domain down regulates ARE-mediated expression and induction. In this report, we have investigated the role of c-Maf (large Maf) containing the transcriptional activation domain in the regulation of ARE-mediated genes expression. The overexpression of c-Maf in human hepatoblastoma (Hep-G2) cells led to the repression of ARE-mediated NQO1 and GST Ya genes expression and induction in response to tert-butyl hydroquinone (t-BHQ). This was in contrast to the role of c-Maf in the activation of Maf recognition element (MARE) mediated p53 gene expression. Deletion of transcriptional activation domain of c-Maf (ĉ-Maf) led to significant loss of MARE-mediated p53 gene expression but had no effect on the repression of ARE-mediated NQO1 gene expression. The overexpression of MafG in Hep-G2 cells repressed both ARE and MARE-mediated genes expression. The co-expression of c-Maf with MafG rescued the MafG repression of MARE but not ARE-mediated gene expression. Band and super shift assays showed the presence of c-Maf in the ARE-nuclear protein complex. Similar assays with in vitro translated proteins revealed that both c-Maf and ĉ-Maf bound to NQO1 gene ARE as homodimers and heterodimers with small Maf but not as heterodimers with Nrf2. Mutational analysis of the NQO1 gene ARE indicated that core ARE sequence is essential for binding of c-Maf leading to repression of NQO1 gene expression. Northern analysis revealed that c-Maf expression increases 2 h after t-BHQ treatment. It reached a plateau at 4 h after t-BHQ treatment. The results together led to the conclusion that c-Maf negatively regulates ARE-mediated detoxifying enzyme genes expression and induction in response to anti-oxidants.
Topics: Antioxidants; Blotting, Northern; DNA Primers; DNA-Binding Proteins; Down-Regulation; Enzyme Activation; Gene Expression Regulation, Enzymologic; Glutathione Transferase; Hepatoblastoma; Humans; Liver Neoplasms; Luciferases; MafG Transcription Factor; NAD(P)H Dehydrogenase (Quinone); Oxidation-Reduction; Promoter Regions, Genetic; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-maf; Quinones; Repressor Proteins; Signal Transduction; Transfection; Tumor Cells, Cultured; Tumor Suppressor Protein p53
PubMed: 12149651
DOI: 10.1038/sj.onc.1205642 -
Oncogene Feb 1997maf is a family of oncogenes originally identified from avian oncogenic retrovirus, AS42, encoding a nuclear bZip transcription factor. We have isolated two maf related...
maf is a family of oncogenes originally identified from avian oncogenic retrovirus, AS42, encoding a nuclear bZip transcription factor. We have isolated two maf related cDNA clones, maf-1 and maf-2, from a rat liver cDNA library. Comparison of the sequence homologies of the proteins encoded by maf-1 and maf-2 with those of c-maf and chicken mafB indicated that maf-1 and maf-2 are the rat homologues of mafB and c-maf, respectively. Both genes are expressed at low levels in a wide variety of rat tissues, including spleen, kidney, muscle and liver. Immunohistochemical studies and in situ hybridization analyses show that maf-1 and maf-2 are strongly expressed in the late stages of chondrocyte development in the femur epiphysis and the rib and limb cartilage of 15 day old (E15) embryo in rat. Cartilage cells, induced by subcutaneous implantation of bone morphogenic protein, also expressed maf-1 and maf-2. In situ hybridization analyses of E15 embryos show that both genes are expressed in the eye lens and the spinal cord as well as the cartilage. However, the expression patterns of maf-1 and maf-2 in lens and spinal cord are different.
Topics: Animals; Base Sequence; Cartilage; Cloning, Molecular; DNA, Complementary; DNA-Binding Proteins; Gene Expression; Immunohistochemistry; In Situ Hybridization; Lens, Crystalline; Liver; Male; Molecular Sequence Data; Oncogene Protein v-maf; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-maf; RNA, Messenger; Rats; Rats, Wistar; Sensitivity and Specificity; Spinal Cord; Transcriptional Activation
PubMed: 9038383
DOI: 10.1038/sj.onc.1200869 -
Journal of Clinical and Experimental... 2019The large Maf transcription factors are expressed in immune cells including macrophages and lymphocytes. To investigate the distribution of Maf expression in human... (Clinical Trial)
Clinical Trial
The large Maf transcription factors are expressed in immune cells including macrophages and lymphocytes. To investigate the distribution of Maf expression in human organs, immunostaining for Maf was performed using sections of several human organs. High Maf expression was seen in the nucleus of macrophages in the gastrointestinal tract and lymph node sinus macrophages (LySMs). Then, we assessed whether Maf expression in LySMs was correlated with CD169 expression and the clinical prognosis in patients with esophageal cancer. Maf expression was associated with CD169 expression, but Maf expression in LySMs was not associated with the clinical course in patients with esophageal cancer. We determined which cytokines stimulate Maf expression using cultured macrophages. Immunocytochemistry showed that Maf expression was significantly elevated by interferon-γ. These results are the first report of Maf expression in human samples. Maf expression may be a marker for the macrophage population in humans.
Topics: Biomarkers, Tumor; Esophageal Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Interferon-gamma; Lymph Nodes; Macrophages; Male; Proto-Oncogene Proteins c-maf; Retrospective Studies; Sialic Acid Binding Ig-like Lectin 1
PubMed: 31564713
DOI: 10.3960/jslrt.19002 -
Molecular and Cellular Biology Oct 1995The avian neural retina (NR) is derived from proliferating neuroectodermal precursors which differentiate after terminal mitosis and become organized in cell strata....
The avian neural retina (NR) is derived from proliferating neuroectodermal precursors which differentiate after terminal mitosis and become organized in cell strata. Proliferation of postmitotic NR cells can be induced by infection with Rous sarcoma virus (RSV) and requires the expression of a functional v-Src protein. QR1 is a retina-specific gene expressed exclusively at the stage of growth arrest and differentiation during retinal development. In NR cells infected with tsPA101, an RSV mutant conditionally defective in pp60v-src mitogenic capacity, QR1 expression is downregulated in proliferating cells at 37 degrees C and is fully restored when the cells become quiescent as a result of pp60v-src inactivation at 41 degrees C. We were able to arrest proliferation of tsPA101-infected quail NR cells expressing an active v-Src protein by serum starvation at 37 degrees C. This allowed us to investigate the role of cell growth in regulating QR1 transcription. We report that QR1 transcription is stimulated in growth-arrested cells at 37 degrees C compared with that in proliferating cells maintained at the same temperature. Growth arrest-dependent stimulation of QR1 transcription requires the integrity of the A box, a previously characterized cis-acting element responsible for QR1 transcriptional stimulation upon v-Src inactivation and during retinal differentiation. We also show that formation of the C1 complex on the A box is increased upon growth arrest by serum starvation in the presence of an active v-Src oncoprotein. Thus, the C1 complex represents an important link between cell cycle and developmental control of QR1 gene transcription during NR differentiation and RSV infection. By using antibodies directed against different Maf proteins of the leucine zipper family and competition with Maf consensus site-containing oligonucleotides in a gel shift assay, we show that the C1 complex is likely to contain a Maf-related protein. We also show that a purified bacterially expressed v-Maf protein is able to bind the A box and that the level of a 43-kDa Maf-related protein is increased upon growth arrest in infected retinal cells. Moreover, ectopic expression of c-mafI, c-mafII, and mafB cDNAs in quiescent tsPA101-infected quail NR cells is able to stimulate transcription of a QR1 reporter gene through the A box. Therefore, QR1 appears to be the first target gene for a Maf-related protein(s) in the NR.
Topics: Amino Acid Sequence; Animals; Avian Proteins; Base Sequence; Cell Differentiation; Cell Division; Cells, Cultured; Coturnix; DNA; DNA-Binding Proteins; Eye Proteins; Gene Expression Regulation, Developmental; Leucine Zippers; MafK Transcription Factor; Molecular Sequence Data; Nuclear Proteins; Oncogene Protein pp60(v-src); Oncogene Protein v-maf; Oncogene Proteins; Oncogene Proteins, Viral; Promoter Regions, Genetic; Retina; Trans-Activators; Transcription Factors; Transcriptional Activation; Viral Proteins
PubMed: 7565708
DOI: 10.1128/MCB.15.10.5563 -
Gene Jul 2002Recent progress in the analysis of transcriptional regulation has revealed the presence of an exquisite functional network comprising the Maf and Cap 'n' collar (CNC)... (Review)
Review
Recent progress in the analysis of transcriptional regulation has revealed the presence of an exquisite functional network comprising the Maf and Cap 'n' collar (CNC) families of regulatory proteins, many of which have been isolated. Among Maf factors, large Maf proteins are important in the regulation of embryonic development and cell differentiation, whereas small Maf proteins serve as obligatory heterodimeric partner molecules for members of the CNC family. Both Maf homodimers and CNC-small Maf heterodimers bind to the Maf recognition element (MARE). Since the MARE contains a consensus TRE sequence recognized by AP-1, Jun and Fos family members may act to compete or interfere with the function of CNC-small Maf heterodimers. Overall then, the quantitative balance of transcription factors interacting with the MARE determines its transcriptional activity. Many putative MARE-dependent target genes such as those induced by antioxidants and oxidative stress are under concerted regulation by the CNC family member Nrf2, as clearly proven by mouse germline mutagenesis. Since these genes represent a vital aspect of the cellular defense mechanism against oxidative stress, Nrf2-null mutant mice are highly sensitive to xenobiotic and oxidative insults. Deciphering the molecular basis of the regulatory network composed of Maf and CNC families of transcription factors will undoubtedly lead to a new paradigm for the cooperative function of transcription factors.
Topics: Amino Acid Sequence; Animals; Base Sequence; DNA-Binding Proteins; Drosophila Proteins; Gene Expression Regulation; Genetic Variation; Humans; Models, Genetic; Molecular Sequence Data; Multigene Family; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-maf; Repressor Proteins; Sequence Homology, Amino Acid; Transcription Factors
PubMed: 12234662
DOI: 10.1016/s0378-1119(02)00788-6