Disease relevance of Mafb

• Brainstems from Mafb(-/-) mice are insensitive to preBötC electrolytic lesion or stimulation and modulation of rhythmogenesis by hypoxia or peptidergic input [1].
• Thus, Kreisler must regulate other unknown genes required for podocyte function and with possible roles in kidney disease [2].
• Here we show that mice deficient for the transcription factor MafB die from central apnea at birth and are defective for respiratory rhythmogenesis in vitro [1].

High impact information on Mafb

• Based on an inversion discovered in the original kr allele, we selected a candidate cDNA highly expressed in the developing caudal hindbrain [3].
• The mouse kreisler (kr) mutation causes segmentation abnormalities in the caudal hindbrain and defective inner ear development [3].
• The identity, expression, and mutant phenotype of kr indicate an early role in axial patterning and provide insights into the molecular and embryologic mechanisms that govern hindbrain and otic development [3].
• This cDNA encodes a basic domain-leucine zipper (bZIP) transcription factor and was confirmed to represent the kr gene by analysis of a second kr allele, generated by chemical mutagenesis, in which a serine is substituted for an asparagine residue conserved in the DNA-binding domain of all known bZIP family members [3].
• These studies demonstrate that Krml1 directly activates expression of Hoxb-3 in r5 in combination with an Ets-related activation site, and suggest that kreisler plays a primary role in regulating segmental identity through Hox genes [4].

Chemical compound and disease context of Mafb

• Furthermore, collateral chemosensory pathways that normally mediate delayed responses to hypoxia and hyperoxia were not functional in kr/kr mice [5].

Biological context of Mafb

• Altered rhombomere-specific gene expression and hyoid bone differentiation in the mouse segmentation mutant, kreisler (kr) [6].
• This site is necessary for enhancer activity and when multimerized it is sufficient to direct a kreisler-like pattern in transgenic embryos [7].
• Deletion analysis localized this activity to a 600 bp fragment that was found to contain a single high-affinity binding site for the Maf bZIP protein Krml1, encoded by the kreisler gene [7].
• We propose that the requirement for the downregulation of segmental kreisler expression prior to neuronal differentiation reflects the stage-specific roles of this gene and its targets [8].
• In situ hybridization with CRABPI, kreisler and EphA4 probes and the pattern of expression of a Wnt1-lacZ transgene show that neural crest cells (NCC) normally destined to the 3rd and 4th arches migrate ectopically [9].

Anatomical context of Mafb

• Novel activities of Mafb underlie its dual role in hindbrain segmentation and regional specification [10].
• kreisler is a recessive mutation resulting in gross malformation of the inner ear of homozygous mice [11].
• We found that the hyoid bone in kr/kr animals exhibited an accessory process on the greater horn (a third arch structure) most easily explained by ectopic development of a second arch structure (the hyoid lesser horn) in an area normally derived from the third arch [6].
• To investigate whether the altered patterns of gene expression we observed in the kr/kr embryonic hindbrain are associated with morphologic changes in the adult, we examined neural crest-derived tissues of the second and third branchial arches, which normally arise from rhombomeres 4 and 6, respectively [6].
• Here we show that mice homozygous for the kr(enu) mutation develop renal disease and that Kreisler is essential for cellular differentiation of podocytes [2].

Associations of Mafb with chemical compounds

• The hindbrain of E8.5 A alpha/A gamma embryos shows a posterior expansion of rhombomere 3 and 4 (R3 and R4) markers, but fails to express kreisler, a normal marker of R5 and R6 [12].
• Zkrml2 shows 72% and 92% identity in its basic leucine zipper domain with mouse Krml1 and zebrafish val, respectively [13].

Regulatory relationships of Mafb

• Examination of Krox-20 expression at stages as early as E8.5 indicates that Krox-20 fails ever to be expressed in its r5 domain in the homozygous kreisler mutant [11].

Other interactions of Mafb

• The expression domain of Hoxb-1 is affected differently from the other genes in kr/kr embryos; its rostral boundary at r3/4 is intact but the caudal boundary is displaced from its normal location at r4/5 to the approximate position of r5/6 [6].
• Our work has revealed novel functions for Mafb, including a positive autoregulatory activity, the capacity to repress Hoxb1 expression, and the capacity to synergise with or antagonise Krox20 activity [10].
• This demonstrates that Hoxa3, along with its paralog Hoxb3, is a direct target of kreisler in the mouse hindbrain [7].
• Conserved and distinct roles of kreisler in regulation of the paralogous Hoxa3 and Hoxb3 genes [7].
• Instead of forming a defined r4, Hoxb1- and Wnt8A-expressing cells are scattered throughout the caudal hindbrain, whereas r5/r8 markers such as kreisler or group 3/4 Hox genes are undetectable or markedly downregulated [14].

Analytical, diagnostic and therapeutic context of Mafb

• Here we demonstrate by Southern blot analysis that mafB is the avian homologue of kr, and present a detailed pattern of its expression during avian and murine embryonic development [15].

References