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Nature Communications Jun 2022While apneas are associated with multiple pathological and fatal conditions, the underlying molecular mechanisms remain elusive. We report that a mutated form of the...
While apneas are associated with multiple pathological and fatal conditions, the underlying molecular mechanisms remain elusive. We report that a mutated form of the transcription factor Mafa (Mafa) that prevents phosphorylation of the Mafa protein leads to an abnormally high incidence of breath holding apneas and death in newborn Mafa mutant mice. This apneic breathing is phenocopied by restricting the mutation to central GABAergic inhibitory neurons and by activation of inhibitory Mafa neurons while reversed by inhibiting GABAergic transmission centrally. We find that Mafa activates the Gad2 promoter in vitro and that this activation is enhanced by the mutation that likely results in increased inhibitory drives onto target neurons. We also find that Mafa inhibitory neurons are absent from respiratory, sensory (primary and secondary) and pontine structures but are present in the vicinity of the hypoglossal motor nucleus including premotor neurons that innervate the geniohyoid muscle, to control upper airway patency. Altogether, our data reveal a role for Mafa phosphorylation in regulation of GABAergic drives and suggest a mechanism whereby reduced premotor drives to upper airway muscles may cause apneic breathing at birth.
Topics: Animals; Apnea; Maf Transcription Factors, Large; Mice; Motor Neurons; Phosphorylation; Promoter Regions, Genetic
PubMed: 35672398
DOI: 10.1038/s41467-022-30825-3 -
Gene Sep 2009c-Maf, which is one of the large Maf transcription factors, can bind to Maf recognition element (MARE) and activates transcription of target genes. Although c-Maf is...
c-Maf, which is one of the large Maf transcription factors, can bind to Maf recognition element (MARE) and activates transcription of target genes. Although c-Maf is expressed in macrophages and directly regulates the expression of interleukin-10, detailed information regarding its function in the null mutant phenotype of tissue macrophages remain unknown. In this study, we demonstrated that c-Maf is specifically expressed in the F4/80 positive fetal liver and adult macrophages. The expression of F4/80, which is a tissue macrophage-specific seven trans-membrane receptor, was dramatically suppressed in the c-Maf-deficient macrophage, whereas the expression of Mac-1 was not affected, suggesting that c-Maf is not necessary for the lineage commitment of macrophages. Luciferase reporter and EMSA showed that c-Maf directly regulates the expression of F4/80 by interacting with the half-MARE site of the F4/80 promoter. These results suggest that c-Maf is required for the F4/80 expression in macrophages in vivo.
Topics: Animals; Antigens, Differentiation; Base Sequence; Cells, Cultured; Embryo, Mammalian; Gene Expression Regulation; Liver; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Proto-Oncogene Proteins c-maf; Sequence Homology, Nucleic Acid
PubMed: 19539733
DOI: 10.1016/j.gene.2009.06.003 -
Genes To Cells : Devoted To Molecular &... Aug 2009The importance of the large Maf transcription factor family has been investigated in lens development in the chick, Xenopus and mammals. Previously we reported that...
The importance of the large Maf transcription factor family has been investigated in lens development in the chick, Xenopus and mammals. Previously we reported that c-maf-deficient mice exhibit severe defects in lens fibre cells. Here, we report the roles of other large Mafs, MafA/L-Maf and MafB, during mouse lens development. MafA/L-Maf and MafB were expressed in lens epithelial cells and fibre cells at E12.5 but had largely disappeared from the lens at E18.5. The lens of mafA-, mafB-deficient and mafA::mafB double-deficient mice developed normally. In c-maf-deficient mice, the pattern of expression of MafA and MafB differed from their expression in wild-type mice. Moreover, the expression of crystallin genes was unchanged in mafA-, mafB- and mafA::mafB double-deficient lens. These results indicate that c-Maf alone is essential for lens development, and that MafA/L-Maf and MafB are dispensable in mice.
Topics: Animals; Cell Proliferation; Chickens; Gene Expression Regulation, Developmental; Immunohistochemistry; Lens, Crystalline; Maf Transcription Factors, Large; MafB Transcription Factor; Mice; Mice, Knockout; Proto-Oncogene Proteins c-maf
PubMed: 19624757
DOI: 10.1111/j.1365-2443.2009.01321.x -
The Journal of Biological Chemistry May 2023MafA and c-Maf are close members of the Maf transcription factor family and indicators of poor prognosis of multiple myeloma (MM). Our previous study finds that the...
MafA and c-Maf are close members of the Maf transcription factor family and indicators of poor prognosis of multiple myeloma (MM). Our previous study finds that the ubiquitin ligase HERC4 induces c-Maf degradation but stabilizes MafA, and the mechanism is elusive. In the present study, we find that HERC4 interacts with MafA and mediates its K63-linked polyubiquitination at K33. Moreover, HERC4 inhibits MafA phosphorylation and its transcriptional activity triggered by glycogen synthase kinase 3β (GSK3β). The K33R MafA variant prevents HERC4 from inhibiting MafA phosphorylation and increases MafA transcriptional activity. Further analyses reveal that MafA can also activate the STAT3 signaling, but it is suppressed by HERC4. Lastly, we demonstrate that lithium chloride, a GSK3β inhibitor, can upregulate HERC4 and synergizes dexamethasone, a typical anti-MM drug, in inhibiting MM cell proliferation and xenograft growth in nude mice. These findings thus highlight a novel regulation of MafA oncogenic activity in MM and provide the rationale by targeting HERC4/GSK3β/MafA for the treatment of MM.
Topics: Animals; Humans; Mice; Cell Proliferation; Dexamethasone; Glycogen Synthase Kinase 3 beta; Lithium Chloride; Maf Transcription Factors, Large; Mice, Nude; Multiple Myeloma; Phosphorylation; Polyubiquitin; STAT3 Transcription Factor; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination; Xenograft Model Antitumor Assays
PubMed: 37028761
DOI: 10.1016/j.jbc.2023.104675 -
Nature Communications Oct 2019Interneurons (INs) coordinate motoneuron activity to generate appropriate patterns of muscle contractions, providing animals with the ability to adjust their body...
Interneurons (INs) coordinate motoneuron activity to generate appropriate patterns of muscle contractions, providing animals with the ability to adjust their body posture and to move over a range of speeds. In Drosophila larvae several IN subtypes have been morphologically described and their function well documented. However, the general lack of molecular characterization of those INs prevents the identification of evolutionary counterparts in other animals, limiting our understanding of the principles underlying neuronal circuit organization and function. Here we characterize a restricted subset of neurons in the nerve cord expressing the Maf transcription factor Traffic Jam (TJ). We found that TJ neurons are highly diverse and selective activation of these different subtypes disrupts larval body posture and induces specific locomotor behaviors. Finally, we show that a small subset of TJ GABAergic INs, singled out by the expression of a unique transcription factors code, controls larval crawling speed.
Topics: Animals; Animals, Genetically Modified; Drosophila; Drosophila Proteins; Embryo, Nonmammalian; Gene Expression Regulation; Gene Silencing; Interneurons; Larva; Locomotion; Maf Transcription Factors, Large; Motor Activity; Proto-Oncogene Proteins; Spinal Nerve Roots; gamma-Aminobutyric Acid
PubMed: 31641138
DOI: 10.1038/s41467-019-12693-6 -
The Journal of International Medical... 2009The c-maf gene expression profile was investigated in normal and osteoarthritic articular cartilage using in situ hybridization, qualitative reverse...
The c-maf gene expression profile was investigated in normal and osteoarthritic articular cartilage using in situ hybridization, qualitative reverse transcription-polymerase chain reaction (RT-PCR) and quantitative real-time RT-PCR. Osteoarthritic samples were obtained from 10 patients undergoing total knee replacement for severe osteoarthritis of the knee joints, and control samples from 10 trauma patients undergoing amputation. Expression of c-maf was significantly up-regulated in osteoarthritic cartilage compared with normal cartilage. Using in situ hybridization, distribution of a specific c-maf mRNA signal was found in the top zone and a decreased signal was found in the lower middle zone and the deep zone in osteoarthritic cartilage. A prominent c-maf mRNA signal was seen particularly in proliferating 'chondrocyte clusters'. In contrast, in normal cartilage almost no c-maf-positive cells were found. These findings suggest that c-maf may be important in chondrocyte hypertrophy and terminal differentiation, and may be involved in the pathogenesis of osteoarthritis.
Topics: Adult; Aged; Chondrocytes; Gene Expression Regulation; Humans; Middle Aged; Osteoarthritis; Proto-Oncogene Proteins c-maf; RNA, Messenger
PubMed: 19215682
DOI: 10.1177/147323000903700115 -
Experimental Animals 2015The members of the MAF family of transcription factors are homologs of v-Maf -the oncogenic component of the avian retrovirus AS42. The MAF family is subdivided into 2...
The members of the MAF family of transcription factors are homologs of v-Maf -the oncogenic component of the avian retrovirus AS42. The MAF family is subdivided into 2 groups, small and large MAFs. To elucidate the role of the large MAF transcription factors in the endocrine pancreas, we analyzed large MAF gene knockout mice. It has been shown that Mafa(-/-) mice develop phenotypes including abnormal islet structure soon after birth. This study revealed that Ins1 and Ins2 transcripts and the protein contents were significantly reduced in Mafa(-/-) mice at embryonic day 18.5. In addition, Mafa(-/-);Mafb(-/-) mice contained less than 10% of the insulin transcript and protein of those of wild-type mice, suggesting that Mafa and Mafb cooperate to maintain insulin levels at the embryonic stage. On the other hand, the number of insulin-positive cells in Mafa(-/-) mice was comparable to that of wild-type mice, and even under a Mafb-deficient background the number of insulin-positive cells was not decreased, suggesting that Mafb plays a dominant role in embryonic β-cell development. We also found that at 20 weeks of age Mafa(-/-);Mafb(+/-) mice showed a higher fasting blood glucose level than single Mafa(-/-) mice. In summary, our results indicate that Mafa is necessary for the maintenance of normal insulin levels even in embryos and that Mafb is important for the maintenance of fasting blood glucose levels in the Mafa-deficient background in adults.
Topics: Animals; Blood Glucose; Fasting; Glucagon; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Maf Transcription Factors, Large; MafB Transcription Factor; Mice, Inbred ICR; Mice, Knockout
PubMed: 25912440
DOI: 10.1538/expanim.15-0001 -
Immunological Reviews Mar 2013Interleukin-22 (IL-22) has important functions in host defense at mucosal surfaces as well as in tissue repair. It is unique as a cytokine that is produced by immune... (Review)
Review
Interleukin-22 (IL-22) has important functions in host defense at mucosal surfaces as well as in tissue repair. It is unique as a cytokine that is produced by immune cells, including T-helper (Th) cell subsets and innate lymphocytes, but acts only on non-hematopoietic stromal cells, in particular epithelial cells, keratinocytes, and hepatocytes. Although IL-22 is beneficial to the host in many infectious and inflammatory disorders, depending on the target tissue it can be pathogenic due to its inherent pro-inflammatory properties, which are further enhanced when IL-22 is released together with other pro-inflammatory cytokines, in particular IL-17. To avoid pathology, IL-22 and IL-17 production have to be controlled tightly and independently. While common factors such as signal transducer and activator of transcription 3 (STAT3) and retinoid orphan receptor γt (RORγt) drive the expression of both cytokines, other factors, such as c-Maf act specifically on IL-22 and enable the separate expression of either cytokine. Here, we discuss the production of IL-22 from various T-cell populations as well as protective versus pathogenic roles of IL-22. Finally, we focus on recent advances in our understanding of the molecular regulation of IL-22 in T cells.
Topics: Animals; Gene Expression Regulation; Humans; Immunity, Innate; Immunity, Mucosal; Interleukin-17; Interleukins; Mice; Nuclear Receptor Subfamily 1, Group F, Member 3; Proto-Oncogene Proteins c-maf; STAT3 Transcription Factor; Signal Transduction; T-Lymphocytes, Helper-Inducer; Interleukin-22
PubMed: 23405899
DOI: 10.1111/imr.12027 -
International Journal of Molecular... Apr 2022Pancreatic β-cells are specialized to properly regulate blood glucose. Maintenance of the mature β-cell phenotype is critical for glucose metabolism, and β-cell... (Review)
Review
Pancreatic β-cells are specialized to properly regulate blood glucose. Maintenance of the mature β-cell phenotype is critical for glucose metabolism, and β-cell failure results in diabetes mellitus. Recent studies provide strong evidence that the mature phenotype of β-cells is maintained by several transcription factors. These factors are also required for β-cell differentiation from endocrine precursors or maturation from immature β-cells during pancreatic development. Because the reduction or loss of these factors leads to β-cell failure and diabetes, inducing the upregulation or inhibiting downregulation of these transcription factors would be beneficial for studies in both diabetes and stem cell biology. Here, we discuss one such factor, i.e., the transcription factor MAFA. MAFA is a basic leucine zipper family transcription factor that can activate the expression of insulin in β-cells with PDX1 and NEUROD1. MAFA is indeed indispensable for the maintenance of not only insulin expression but also function of adult β-cells. With loss of MAFA in type 2 diabetes, β-cells cannot maintain their mature phenotype and are dedifferentiated. In this review, we first briefly summarize the functional roles of MAFA in β-cells and then mainly focus on the molecular mechanism of cell fate conversion regulated by MAFA.
Topics: Cell Differentiation; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin-Secreting Cells; Maf Transcription Factors, Large
PubMed: 35562869
DOI: 10.3390/ijms23094478 -
European Journal of Endocrinology Nov 2006Type 2 diabetes is primarily associated with insulin resistance and beta-cell dysfunction. Maintenance of functional mature beta-cells is imperative for ensuring glucose... (Review)
Review
Type 2 diabetes is primarily associated with insulin resistance and beta-cell dysfunction. Maintenance of functional mature beta-cells is imperative for ensuring glucose homeostasis. This can be achieved by optimal expression of key transcription factors that are required for normal pancreatic development and maintaining beta-cell function. Defining the regulation of transcription factors as well as their regulation of important beta-cell genes like insulin will provide further insight into elucidating the mechanisms leading to beta-cell dysfunction.
Topics: Basic Helix-Loop-Helix Transcription Factors; Eye Proteins; Hepatocyte Nuclear Factor 1-alpha; Hepatocyte Nuclear Factor 3-beta; Homeodomain Proteins; Humans; Insulin-Secreting Cells; Maf Transcription Factors; Nerve Tissue Proteins; PAX6 Transcription Factor; Paired Box Transcription Factors; Pancreas; Repressor Proteins; Trans-Activators; Transcription Factors
PubMed: 17062882
DOI: 10.1530/eje.1.02277