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Gene Jul 2016The small Maf proteins (sMafs) are basic region leucine zipper (bZIP)-type transcription factors. The basic region of the Maf family is unique among the bZIP factors,... (Review)
Review
The small Maf proteins (sMafs) are basic region leucine zipper (bZIP)-type transcription factors. The basic region of the Maf family is unique among the bZIP factors, and it contributes to the distinct DNA-binding mode of this class of proteins. MafF, MafG and MafK are the three vertebrate sMafs, and no functional differences have been observed among them in terms of their bZIP structures. sMafs form homodimers by themselves, and they form heterodimers with cap 'n' collar (CNC) proteins (p45 NF-E2, Nrf1, Nrf2, and Nrf3) and also with Bach proteins (Bach1 and Bach2). Because CNC and Bach proteins cannot bind to DNA as monomers, sMafs are indispensable partners that are required by CNC and Bach proteins to exert their functions. sMafs lack the transcriptional activation domain; hence, their homodimers act as transcriptional repressors. In contrast, sMafs participate in transcriptional activation or repression depending on their heterodimeric partner molecules and context. Mouse genetic analyses have revealed that various biological pathways are under the regulation of CNC-sMaf heterodimers. In this review, we summarize the history and current progress of sMaf studies in relation to their partners.
Topics: Animals; DNA; DNA-Binding Proteins; Disease; History, 20th Century; History, 21st Century; Humans; MafF Transcription Factor; MafG Transcription Factor; MafK Transcription Factor; Mice; Nuclear Proteins; Repressor Proteins
PubMed: 27058431
DOI: 10.1016/j.gene.2016.03.058 -
Acta Physiologica (Oxford, England) Feb 2022Reduced expression of exocytotic genes is associated with functional defects in insulin exocytosis contributing to impaired insulin secretion and type 2 diabetes (T2D)...
AIMS
Reduced expression of exocytotic genes is associated with functional defects in insulin exocytosis contributing to impaired insulin secretion and type 2 diabetes (T2D) development. MAFA and MAFB transcription factors regulate β-cell physiology, and their gene expression is reduced in T2D β cells. We investigate if loss of MAFA and MAFB in human β cells contributes to T2D progression by regulating genes required for insulin exocytosis.
METHODS
Three approaches were performed: (1) RNAseq analysis with the focus on exocytosis-related genes in MafA mouse islets, (2) correlational analysis between MAFA, MAFB and exocytosis-related genes in human islets and (3) MAFA and MAFB silencing in human islets and EndoC-βH1 cells followed by functional in vitro studies.
RESULTS
The expression of 30 exocytosis-related genes was significantly downregulated in MafA mouse islets. In human islets, the expression of 29 exocytosis-related genes correlated positively with MAFA and MAFB. Eight exocytosis-related genes were downregulated in MafA mouse islets and positively correlated with MAFA and MAFB in human islets. From this analysis, the expression of RAB3A, STXBP1, UNC13A, VAMP2, NAPA, NSF, STX1A and SYT7 was quantified after acute MAFA or MAFB silencing in EndoC-βH1 cells and human islets. MAFA and MAFB silencing resulted in impaired insulin secretion and reduced STX1A, SYT7 and STXBP1 (EndoC-βH1) and STX1A (human islets) mRNA expression. STX1A and STXBP1 protein expression was also impaired in islets from T2D donors which lack MAFA expression.
CONCLUSION
Our data indicate that STXBP1 and STX1A are important MAFA/B-regulated exocytosis genes which may contribute to insulin exocytosis defects observed in MAFA-deficient human T2D β cells.
Topics: Animals; Diabetes Mellitus, Type 2; Exocytosis; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Maf Transcription Factors, Large; MafB Transcription Factor; Mice
PubMed: 34978761
DOI: 10.1111/apha.13761 -
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 -
Cell Reports Jan 2019Mafb and c-Maf transcription factor (TF) expression is enriched in medial ganglionic eminence (MGE) lineages, beginning in late-secondary progenitors and continuing into...
Mafb and c-Maf transcription factor (TF) expression is enriched in medial ganglionic eminence (MGE) lineages, beginning in late-secondary progenitors and continuing into mature parvalbumin (PV) and somatostatin (SST) interneurons. However, the functions of Maf TFs in MGE development remain to be elucidated. Herein, Mafb and c-Maf were conditionally deleted, alone and together, in the MGE and its lineages. Analyses of Maf mutant mice revealed redundant functions of Mafb and c-Maf in secondary MGE progenitors, where they repress the generation of SST cortical and hippocampal interneurons. By contrast, Mafb and c-Maf have distinct roles in postnatal cortical interneuron (CIN) morphological maturation, synaptogenesis, and cortical circuit integration. Thus, Mafb and c-Maf have redundant and opposing functions at different steps in CIN development.
Topics: Action Potentials; Animals; Animals, Newborn; Apoptosis; Cell Lineage; Cell Membrane; Cell Movement; Cell Proliferation; Cerebral Cortex; Hippocampus; Interneurons; MafB Transcription Factor; Median Eminence; Mice, Knockout; Neurites; Neurogenesis; Parvalbumins; Proto-Oncogene Proteins c-maf; Somatostatin; Synapses
PubMed: 30699346
DOI: 10.1016/j.celrep.2019.01.031 -
Human Mutation Apr 2018Mutations in the transcription factor genes FOXE3, HSF4, MAF, and PITX3 cause congenital lens defects including cataracts that may be accompanied by defects in other... (Review)
Review
Mutations in the transcription factor genes FOXE3, HSF4, MAF, and PITX3 cause congenital lens defects including cataracts that may be accompanied by defects in other components of the eye or in nonocular tissues. We comprehensively describe here all the variants in FOXE3, HSF4, MAF, and PITX3 genes linked to human developmental defects. A total of 52 variants for FOXE3, 18 variants for HSF4, 20 variants for MAF, and 19 variants for PITX3 identified so far in isolated cases or within families are documented. This effort reveals FOXE3, HSF4, MAF, and PITX3 to have 33, 16, 18, and 7 unique causal mutations, respectively. Loss-of-function mutant animals for these genes have served to model the pathobiology of the associated human defects, and we discuss the currently known molecular function of these genes, particularly with emphasis on their role in ocular development. Finally, we make the detailed FOXE3, HSF4, MAF, and PITX3 variant information available in the Leiden Online Variation Database (LOVD) platform at https://www.LOVD.nl/FOXE3, https://www.LOVD.nl/HSF4, https://www.LOVD.nl/MAF, and https://www.LOVD.nl/PITX3. Thus, this article informs on key variants in transcription factor genes linked to cataract, aphakia, corneal opacity, glaucoma, microcornea, microphthalmia, anterior segment mesenchymal dysgenesis, and Ayme-Gripp syndrome, and facilitates their access through Web-based databases.
Topics: Animals; Cataract; Eye Abnormalities; Facies; Forkhead Transcription Factors; Growth Disorders; Hearing Loss, Sensorineural; Heat Shock Transcription Factors; Homeodomain Proteins; Humans; Intellectual Disability; Mutation; Proto-Oncogene Proteins c-maf; Transcription Factors
PubMed: 29314435
DOI: 10.1002/humu.23395 -
Diabetes/metabolism Research and Reviews Nov 2015Cellular muscular aponeurotic fibrosarcoma (c-Maf) is a member of the large macrophage-activating factor family. C-Maf plays important roles in the morphogenetic... (Review)
Review
Cellular muscular aponeurotic fibrosarcoma (c-Maf) is a member of the large macrophage-activating factor family. C-Maf plays important roles in the morphogenetic processes and cellular differentiation of the lens, kidneys, liver, T cells and nervous system, and it is particularly important in pancreatic islet and erythroblastic island formation. However, the exact role of c-Maf remains to be elucidated. In this review, we summarize the research to clarify the functions of c-Maf in the cellular development and differentiation. The expression of c-Maf is higher in pancreatic duct cells than in pancreatic islet cells. Therefore, we suggest that pancreatic duct cells may be converted to the functional insulin-secreting cells by regulating c-Maf.
Topics: Cell Differentiation; Humans; Insulin-Secreting Cells; Islets of Langerhans; Pancreas; Pancreatic Ducts; Proto-Oncogene Proteins c-maf
PubMed: 26122665
DOI: 10.1002/dmrr.2676 -
Biology of Reproduction Oct 2021Testis differentiation is initiated when Sry in pre-Sertoli cells directs the gonad toward a male-specific fate. Sertoli cells are essential for testis development, but...
Testis differentiation is initiated when Sry in pre-Sertoli cells directs the gonad toward a male-specific fate. Sertoli cells are essential for testis development, but cell types within the interstitial compartment, such as immune and endothelial cells, are also critical for organ formation. Our previous work implicated macrophages in fetal testis morphogenesis, but little is known about genes underlying immune cell development during organogenesis. Here, we examine the role of the immune-associated genes Mafb and Maf in mouse fetal gonad development, and we demonstrate that deletion of these genes leads to aberrant hematopoiesis manifested by supernumerary gonadal monocytes. Mafb; Maf double knockout embryos underwent initial gonadal sex determination normally, but exhibited testicular hypervascularization, testis cord formation defects, Leydig cell deficit, and a reduced number of germ cells. In general, Mafb and Maf alone were dispensable for gonad development; however, when both genes were deleted, we observed significant defects in testicular morphogenesis, indicating that Mafb and Maf work redundantly during testis differentiation. These results demonstrate previously unappreciated roles for Mafb and Maf in immune and vascular development and highlight the importance of interstitial cells in gonadal differentiation.
Topics: Animals; Embryo, Mammalian; MafB Transcription Factor; Male; Mice; Myeloid Cells; Organogenesis; Proto-Oncogene Proteins c-maf; Testis
PubMed: 34007995
DOI: 10.1093/biolre/ioab098 -
American Journal of Medical Genetics.... Oct 2022Pathogenic variants in the v-maf avian musculoaponeurotic fibrosarcoma oncogene homologue (MAF) encoding a transcription factor (from a unique subclass of basic leucine...
Pathogenic variants in the v-maf avian musculoaponeurotic fibrosarcoma oncogene homologue (MAF) encoding a transcription factor (from a unique subclass of basic leucine zipper transcription factors) are associated with isolated congenital cataracts (CCs) and Aymé-Gripp syndrome (AYGRPS). We collected detailed disease histories from, and performed comprehensive ophthalmic and systemic examinations in 269 patients with CCs; we then performed whole-exome sequencing. Pathogenicity assessments were evaluated using multiple predictive tools. The clinical validities of the reported gene-disease relationships for MAF genes (MAF-CCs and MAF-AYGRPS) were assessed using the ClinGen gene curation framework. We identified two novel (c.173C>A, p.Thr58Asn and c.947T>C, p. Leu316Pro) variants and one known (c.173C>T, p.Thr58Ile) MAF missense variant in three patients. We described novel phenotypes including cleft palate, macular hypoplasia, and retinal neovascularization in the peripheral avascular area and analyzed the genotype-phenotype correlations. We demonstrated associations of variants in the MAF C-terminal DNA-binding domain with CCs and associations of variants in the N-terminal transactivation domain of MAF with AYGRPS. We thus expand the genotypic and phenotypic spectrum of the MAF gene. The ClinGen gene curation framework results suggested that variants in different domains of MAF are associated with different diseases.
Topics: Cataract; China; Facies; Genotype; Growth Disorders; Hearing Loss, Sensorineural; Humans; Intellectual Disability; Phenotype; Proto-Oncogene Proteins c-maf
PubMed: 36097645
DOI: 10.1002/ajmg.a.62947 -
Journal of Pediatric Urology Feb 2021Hypospadias is the second most common congenital malformation in males. Although the aetiology of hypospadias is not clear, it is generally thought to be affected by...
BACKGROUND
Hypospadias is the second most common congenital malformation in males. Although the aetiology of hypospadias is not clear, it is generally thought to be affected by both genetic and environmental endocrine-disrupting factors that affect the development of the urethra, leading to deformity.
OBJECTIVE
To investigate the difference in expression of the transcription factor Mafb in hypospadias and normal penile tissues and to assess whether it is related to the occurrence of hypospadias.
STUDY DESIGN
Penile tissue was obtained from children with hypospadias who underwent surgical repair at the Children's Hospital of Chongqing Medical University. Patients diagnosed with undescended testicles, intersex status or endocrine abnormalities were excluded from the study. Twenty-five cases with hypospadias (average 3.5 years old) and 15 cases with circumcisions (as control) (average 5 years old) were included in this study. Real-time quantitative polymerase chain reaction, Immunochemistry and Western blot were used to detect the expression of Mafb.
RESULTS
Mafb mRNA expressions in the prepuce of cases with hypospadias was significantly reduced compared with that in the controls [(1.179 ± 0.1275), (0.6652 ± 0.07506), p < 0.05)]. Hypospadias cases also showed decreased Mafb protein expression in the preputial subcutaneous mesenchymal cell layer. Mafb protein levels were significantly decreased in those with hypospadias compared with controls [(1.932 ± 0.1139), (1.006 ± 0.03312), p < 0.05]. However, no such differences were found in Mafb expression between subjects with mild and severe hypospadias.
DISCUSSION
Compared to the normal foreskin, expression of the Mafb gene was down-regulated at both mRNA and protein levels, which was consistent with our RNA-seq sequencing results in Diethylhexyl phthalate (DEHP)-induced hypospadias rats. This study is the first to report abnormal expression of Mafb in the preputial tissue of hypospadias cases. An in-depth study of the relationship between Mafb and cell proliferation, apoptosis, and urethra development may reveal the pathogenesis of hypospadias.
CONCLUSION
Expression of the Mafb gene and protein in the foreskin of children with hypospadias is lower than that in normal foreskin. We postulate that such abnormal expression of the Mafb gene may be related to the occurrence of hypospadias and that this abnormal expression may affect the development of the urethra during the embryonic period.
Topics: Animals; Child; Foreskin; Humans; Hypospadias; MafB Transcription Factor; Male; Oncogene Proteins; Penis; Rats; Urethra
PubMed: 33268316
DOI: 10.1016/j.jpurol.2020.10.006 -
Cancers May 2021Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the clonal expansion of malignant plasma cells within the bone marrow. Activator Protein-1... (Review)
Review
Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the clonal expansion of malignant plasma cells within the bone marrow. Activator Protein-1 (AP-1) transcription factors (TFs), comprised of the JUN, FOS, ATF and MAF multigene families, are implicated in a plethora of physiologic processes and tumorigenesis including plasma cell differentiation and MM pathogenesis. Depending on the genetic background, the tumor stage, and cues of the tumor microenvironment, specific dimeric AP-1 complexes are formed. For example, AP-1 complexes containing Fra-1, Fra-2 and B-ATF play central roles in the transcriptional control of B cell development and plasma cell differentiation, while dysregulation of AP-1 family members c-Maf, c-Jun, and JunB is associated with MM cell proliferation, survival, drug resistance, bone marrow angiogenesis, and bone disease. The present review article summarizes our up-to-date knowledge on the role of AP-1 family members in plasma cell differentiation and MM pathophysiology. Moreover, it discusses novel, rationally derived approaches to therapeutically target AP-1 TFs, including protein-protein and protein-DNA binding inhibitors, epigenetic modifiers and natural products.
PubMed: 34066181
DOI: 10.3390/cancers13102326