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At least 19 recordsLinked to original sources
PubMed2001

A population of caudally migrating cranial neural crest cells: functional and evolutionary implications.

The deployment of the cranial neural crest is central to the patterning of the skeletomuscular elements of the vertebrate head, with cranial muscles invariably attaching to skeletal elements formed by crest from the same axial level. Here we demonstrate, through gene expression analysis, ablation studies and fate-mapping, the existence of a population of caudally migrating cranial crest that arise from the postotic neural tube. As with the rest of the postotic crest, these cells express the transcription factor Mafb, and this marker can be used to highlight their posterior migration. They pass out between the anterior somite and the otic vesicle, before turning caudally and running along the base of the somites. With long-term fate mapping, we show that these cells migrate to the clavicle and settle at the site of formation of the attachment point for the cleidohyoid muscle. As such, the influence of the cranial neural crest in organising skeletomuscular connectivity seems to extend beyond the head into the trunk. These results are of further importance as they help explain how, even though the pectoral girdle and the skull became physically dissociated during tetrapod evolution, skeletomuscular connectivity has been maintained.

Animals↗
PubMed1997

The expression pattern of the mafB/kr gene in birds and mice reveals that the kreisler phenotype does not represent a null mutant.

The recessive mouse mutation kreisler affects hindbrain segmentation and inner ear development in homozygous mice. The mouse gene affected by the mutation was found to encode a basic domain leucine-zipper (bZIP)-type transcription factor of the Maf-family named kr (Cordes, S.P. and Barsh, G.S. (1994) Cell 79, 1025-1034). The avian bZIP transcription factor mafB, which shows high homology to kr, has been identified as an interaction partner of c-Ets 1 (Sieweke, M.H., Tekotte, M.H., Frampton, J. and Graf, T. (1996) Cell 85, 49-60). 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. Consistent with the kreisler phenotype, mafB is expressed in avians in the tissues which are affected by the mouse mutation: rhombomeres 5 and 6 (r5 and r6) and the neural crest derived from these rhombomeres. However, our analysis reveals a variety of additional expression sites: mafB/kr expression persists in vestibular and acoustic nuclei and is also observed in differentiating neurons of the spinal cord and brain stem. Restricted expression sites are found in the mesonephros, the perichondrium, and in the hemopoietic system. Since these expression sites are conserved between mouse and chicken we reexamined homozygous kreisler mice for unrevealed phenotypes in the hemopoietic system. However, peritoneal macrophages from homozygous kreisler mice were found to be functionally normal and still expressed mafB/kr. Other adult tissues examined from homozygous kreisler mice had also not lost mafB/kr expression. Our results thus indicate that the kreisler mutation involves a tissue specific gene inactivation and suggest additional roles for mafB/kr in later developmental and differentiation processes that are not revealed by the mutation.

Animals↗
PubMed2003

Analysis of hindbrain patterning defects caused by the kreisler(enu) mutation reveals multiple roles of Kreisler in hindbrain segmentation.

The embryonic hindbrain is subdivided into eight subunits, termed rhombomeres (r1-r8). The Kreisler (Krml1/MafB/val) transcription factor is expressed in and essential for patterning rhombomeres 5 and 6. Here, we have shown that in the chemically induced kreisler(enu) (kr(enu)) allele, a point mutation in the DNA binding domain abolishes or severely reduces Kreisler-dependent transcription. Comparison of kr(enu)/kr(enu) embryos with those homozygous for the classic kreisler (kr) mutation has reconciled past discrepancies and revealed multiple roles of Kreisler in hindbrain segmentation. These analyses demonstrate that Kreisler is required for maintenance and expansion but not initiation of the Krox20 expressing r5 domain. The differences in the "r5-like" phenotype of kr(enu)/kr(enu) and kr/kr mouse embryos, and zebrafish carrying mutations in the Kreisler orthologue valentino (val) suggest that Kreisler performs many of its r5-specific functions by associating with other proteins. By contrast, kr/kr and kr(enu)/kr(enu) mouse and val-/- zebrafish embryos all exhibit indistinguishable defects in r6 specification. Thus, transcriptionally active Kreisler is required for r6 specification. Unlike mouse kr(enu)/kr(enu) and zebrafish val-/- embryos, kr/kr embryos exhibited anterior defects. We determined that the kr chromosomal inversion caused ectopic Kreisler expression in r3 of kr/kr and kr/+ embryos. Hence, Kreisler regulates maintenance and expansion of r5 and specification of r6 but is not required for r3 development.

Alleles↗
PubMed1999

The role of kreisler in segmentation during hindbrain development.

The mouse kreisler gene is expressed in rhombomeres (r) 5 and 6 during neural development and kreisler mutants have patterning defects in the hindbrain that are not fully understood. Here we analyzed this phenotype with a combination of genetic, molecular, and cellular marking techniques. Using Hox/lacZ transgenic mice as reporter lines and by analyzing Eph/ephrin expression, we have found that while r5 fails to form in these mice, r6 is present. This shows that kreisler has an early role in the formation of r5. We also observed patterning defects in r3 and r4 that are outside the normal domain of kreisler expression. In both heterozygous and homozygous kreisler embryos some r5 markers are induced in r3, suggesting that there is a partial change in r3 identity that is not dependent upon the loss of r5. To investigate the cellular character of r6 in kreisler embryos we performed heterotopic grafting experiments in the mouse hindbrain to monitor its mixing properties. Control experiments revealed that cells from even- or odd-numbered segments only mixed freely with themselves, but not with cells of opposite character. Transposition of cells from the r6 territory of kreisler mutants reveals that they adopt mature r6 characteristics, as they freely mix only with cells from even-numbered rhombomeres. Analysis of Phox2b expression shows that some aspects of later neurogenesis in r6 are altered, which may be associated with the additional roles of kreisler in regulating segmental identity. Together these results suggest that the formation of r6 has not been affected in kreisler mutants. This analysis has revealed phenotypic and mechanistic differences between kreisler and its zebrafish equivalent valentino. While valentino is believed to subdivide preexisting segmental units, in the mouse kreisler specifies a particular segment. The formation of r6 independent of r5 argues against a role of kreisler in prorhombomeric segmentation of the mouse hindbrain. We conclude that the mouse kreisler gene regulates multiple steps in segmental patterning involving both the formation of segments and their A-P identity.

Animals↗
PubMed1999

Expression of Zkrml2, a homologue of the Krml1/val segmentation gene, during embryonic patterning of the zebrafish (Danio rerio).

We have identified Zkrml2, a novel homologue of the segmentation gene Krml/val in zebrafish (Danio rerio). Zkrml2 shows 72% and 92% identity in its basic leucine zipper domain with mouse Krml1 and zebrafish val, respectively. Zkrml2 is expressed coincident with MyoD throughout the somites starting at the three somite stage, becomes restricted to the dermomyotome, and subsequently disappears. Transient expression is also detected in the reticulospinal and oculomotor neurons. Zkrml2 maps to the Oregon linkage group 11 (Boston Linkage group 14) with no mapped zebrafish mutations nearby.

Amino Acid Sequence↗
PubMed1997

Development of branchiomotor neurons in zebrafish.

The mechanisms underlying neuronal specification and axonogenesis in the vertebrate hindbrain are poorly understood. To address these questions, we have employed anatomical methods and mutational analysis to characterize the branchiomotor neurons in the zebrafish embryo. The zebrafish branchiomotor system is similar to those in the chick and mouse, except for the location of the nVII and nIX branchiomotor neurons. Developmental analyses of genes expressed by branchiomotor neurons suggest that the different location of the nVII neurons in the zebrafish may result from cell migration. To gain insight into the mechanisms underlying the organization and axonogenesis of these neurons, we examined the development of the branchiomotor pathways in neuronal mutants. The valentino b337 mutation blocks the formation of rhombomeres 5 and 6, and severely affects the development of the nVII and nIX motor nuclei. The cyclops b16 mutation deletes ventral midline cells in the neural tube, and leads to a severe disruption of most branchiomotor nuclei and axon pathways. These results demonstrate that rhombomere-specific cues and ventral midline cells play important roles in the development of the branchiomotor pathways.

Animals↗
PubMed1998

Equivalence in the genetic control of hindbrain segmentation in fish and mouse.

The vertebrate hindbrain is subdivided into a series of rhombomeres whose segmental organization serves to pattern the architecture and innervation of the developing head. The zebrafish gene valentino is required cell-autonomously in the development of rhombomeres 5 and 6, and valentino mutants lack visible hindbrain segmentation caudal to the r3/4 boundary (Moens, C. B., Yan, Y.-L., Appel, B., Force, A. G., and Kimmel, C. B. (1996) Development 122, 3981-3990). Here we show that valentino is the zebrafish homologue of the mouse segmentation gene kreisler, which encodes a bZip transcription factor. The valentino gene is expressed in a manner consistent with its proposed role in subdividing rhombomeres 5 and 6 from their common precursor 'proto-segment' in the presumptive hindbrain, a process that we also demonstrate is reflected in the normal order of appearance of rhombomere boundaries. As well as having similar phenotypes with respect to visible hindbrain segmentation and patterns of marker gene expression, valentino and kreisler mutants have similar pharyngeal arch and inner ear defects, consistent with a conserved role for this gene in hindbrain segmentation and in patterning of the head periphery.

Amino Acid Sequence↗
PubMed2002

spiel ohne grenzen/pou2 is required for zebrafish hindbrain segmentation.

Segmentation of the vertebrate hindbrain leads to the formation of a series of rhombomeres with distinct identities. In mouse, Krox20 and kreisler play important roles in specifying distinct rhombomeres and in controlling segmental identity by directly regulating rhombomere-specific expression of Hox genes. We show that spiel ohne grenzen (spg) zebrafish mutants develop rhombomeric territories that are abnormal in both size and shape. Rhombomere boundaries are malpositioned or absent and the segmental pattern of neuronal differentiation is perturbed. Segment-specific expression of hoxa2, hoxb2 and hoxb3 is severely affected during initial stages of hindbrain development in spg mutants and the establishment of krx20 (Krox20 ortholog) and valentino (val; kreisler ortholog) expression is impaired. spg mutants carry loss-of-function mutations in the pou2 gene. pou2 is expressed at high levels in the hindbrain primordium of wild-type embryos prior to activation of krx20 and val. Widespread overexpression of Pou2 can rescue the segmental krx20 and val domains in spg mutants, but does not induce ectopic expression of these genes. This suggests that spg/pou2 acts in a permissive manner and is essential for normal expression of krx20 and val. We propose that spg/pou2 is an essential component of the regulatory cascade controlling hindbrain segmentation and acts before krx20 and val in the establishment of rhombomere precursor territories.

Animals↗
PubMed2006

Development of macrophages with altered actin organization in the absence of MafB.

In the hematopoietic system the bZip transcription factor MafB is selectively expressed at high levels in monocytes and macrophages and promotes macrophage differentiation in myeloid progenitors, whereas a dominant-negative allele can inhibit this process. To analyze the requirement of MafB for macrophage development, we generated MafB-deficient mice and, due to their neonatal lethal phenotype, analyzed macrophage differentiation in vitro, in the embryo, and in reconstituted mice. Surprisingly we observed in vitro differentiation of macrophages from E14.5 fetal liver (FL) cells and E18.5 splenocytes. Furthermore we found normal numbers of F4/80(+)/Mac-1(+) macrophages and monocytes in fetal liver, spleen, and blood as well as in bone marrow, spleen, and peritoneum of adult MafB(-/-) FL reconstituted mice. MafB(-/-) macrophages showed intact basic macrophage functions such as phagocytosis of latex beads or Listeria monocytogenes and nitric oxide production in response to lipopolysaccharide. By contrast, MafB(-/-) macrophages expressed increased levels of multiple genes involved in actin organization. Consistent with this, phalloidin staining revealed an altered morphology involving increased numbers of branched protrusions of MafB(-/-) macrophages in response to macrophage colony-stimulating factor. Together these data point to an unexpected redundancy of MafB function in macrophage differentiation and a previously unknown role in actin-dependent macrophage morphology.

Actins↗
PubMed2000

MafB is an inducer of monocytic differentiation.

The bZip transcription factor MafB is expressed specifically in the myeloid lineage of the hematopoietic system and is up-regulated successively during myeloid differentiation from multipotent progenitors to macrophages. Here we report that this induction reflects an essential role of MafB in early myeloid and monocytic differentiation. We observed that the expression of MafB in transformed chicken hematopoietic precursors dramatically increases the proportion of myeloid colony formation at the expense of multipotent progenitor-type colonies. In addition, the overexpression of MafB in transformed myeloblasts stimulates the rapid formation of macrophages, as judged by morphology, surface marker expression and functional criteria. MafB-induced macrophages exhibit typical levels of phagocytic activity and nitric oxide release after activation by lipopolysaccharide. By contrast, overexpression of the myeloid transcription factor PU.1 in these cells does not induce macrophage differentiation. Furthermore, a dominant-negative allele of MafB inhibits both myeloid colony formation and the differentiation of myeloblasts into macrophages. Taken together, our results indicate that MafB induction is a specific and essential determinant of the monocytic program in hematopoietic cells.

Amino Acid Sequence↗
PubMed2003

Novel activities of Mafb underlie its dual role in hindbrain segmentation and regional specification.

The bZip transcription factor Mafb is expressed in two segments of the developing vertebrate hindbrain: the rhombomeres 5 and 6. Loss of Mafb expression in the mouse mutant kreisler leads to elimination of r5 and to alterations of r6 regional identity. Here, we further investigated the role of Mafb in hindbrain patterning using gain-of-function experiments in the chick embryo. 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. These different activities appear to be spatially restricted in the hindbrain, presumably due to interactions with other factors. Reinvestigation of the kreisler mutation indicated that it also results in an ectopic activation of Mafb in rhombomere 3, accounting for the previously described molecular alterations of this rhombomere in the mutant. Together, these data allow us to refine our view of the dual function of Mafb in both segmentation and specification of anteroposterior identity in the hindbrain.

Animals↗
PubMed1999

Cloning and characterization of promoter of the mouse mafB gene.

The MafB transcription factor plays a pivotal role in controlling the development and differentiation. The author reports the isolation and analysis of genomic clone of the mouse mafB gene. The gene lacks intron structure, at least, within its coding and 5'-untranslated sequences that are similar to the chicken mafB gene. RNA protection analysis determined one transcription initiation site of the gene at 389-bp upstream from the translation initiation site. Sequence analysis showed that the 5'-flanking region upstream to the ATG codon did not contain a conventional TATA box. A TATA-like sequence (5'-GATAAAA-3') and an inverted CCAAT-box (5'-ATTGG-3') were found to be located at nucleotide -31 and -86, referring to the transcription initiation site, respectively. Upstream to these sequences, there were several potential regulatory elements, including two GC-boxes (5'-GGGCGG-3': from -148 to -143; and from -123 to -118), and a palindromic sequence (5'-GTCAGCTGAC-3': from -164 to -155) which contained two halves-MARE (Maf recognition element), 5'-GCTGAC-3', and an E-box (5'-CAGCTG-3'). Promoter activity of the 5'-flanking region was analyzed by reporter transfection assay, which suggested that these segments were an important transcriptional activator. It was also suggested that MyoD transactivated the mouse mafB promoter and this gene was positively autoregulated by its product, MafB.

Animals↗
PubMed2003

The mouse mafB 5'-upstream fragment directs gene expression in myelomonocytic cells, differentiated macrophages and the ventral spinal cord in transgenic mice.

The b-Zip transcription factor MafB is an essential determinant of neural development and an inducer of monocytic differentiation. The MafB protein is expressed in a variety of tissues including the developing spinal cord, retina, myelomonocytic lineages of hematopoietic cells, and peritoneal macrophages. However, the tissue-specific regulatory mechanism of mafB gene expression and its biological relevance have not been examined in detail. Here, we report, for the first time, analysis of the regulatory mechanism and tissue-specific expression of the mafB gene in vivo using transgenic mice. A transgene, containing the 8.2-kb sequence flanking the 5' end of the mafB exon, directed the expression of a GFP reporter gene specifically in the retina, myelomonocytic lineages of hematopoietic cells, peritoneal macrophages and the ventral spinal cord. In situ hybridization analysis showed that the reporter gene expression specifically recapitulates the endogenous expression profile of mafB in the retina and spinal cord. FACS analysis revealed that the Gr-1, Mac-1 and F4/80 antigens were present on most of the GFP-positive hematopoietic cells from transgenic adult bone marrow and spleen. On the other hand, B220 CD4, 8, and Ter119 cells were almost absent from among the GFP-positive cells examined. These observations suggest that gene regulatory regions located in the 8.2-kb upstream region of mafB are responsible for directing mafB expression in the retina, myelomonocytic lineages, peritoneal macrophages and the ventral spinal cord.

5' Untranslated Regions↗
PubMed2004

Low-density lipoprotein receptor-related protein interacts with MafB, a regulator of hindbrain development.

The intracellular domain (ICD) of the low-density lipoprotein receptor-related protein (LRP) functionally interacts with adaptor proteins both as an integral part of the receptor polypeptide and after proteolytic release. Identification of such adaptors has been difficult because the ICD is self-activating in conventional transcription factor-based yeast two-hybrid screens. We adopted an alternative screen for the ICD that depends on the activation of the Ras-signaling pathway and uncovered the transcription factor MafB as novel ICD interacting protein. MafB is a regulator of hindbrain segmentation and interacts with the ICD through a leucine zipper domain. The ICD co-localizes with MafB to the nucleus and negatively regulates its transcriptional activity, suggesting a possible role for LRP in brain development.

Amino Acid Sequence↗
PubMed2003

MafB deficiency causes defective respiratory rhythmogenesis and fatal central apnea at birth.

The genetic basis for the development of brainstem neurons that generate respiratory rhythm is unknown. 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. MafB is expressed in a subpopulation of neurons in the preBötzinger complex (preBötC), a putative principal site of rhythmogenesis. Brainstems from Mafb(-/-) mice are insensitive to preBötC electrolytic lesion or stimulation and modulation of rhythmogenesis by hypoxia or peptidergic input. Furthermore, in Mafb(-/-) mice the preBötC, but not major neuromodulatory groups, presents severe anatomical defects with loss of cellularity. Our results show an essential role of MafB in central respiratory control, possibly involving the specification of rhythmogenic preBötC neurons.

Action Potentials↗
PubMed2002

c-Maf, the gammaD-crystallin Maf-responsive element and growth factor regulation.

The transcription factor c-Maf has been suggested to regulate the activity of gamma-crystallin promoters in lens fibre cells. We here show that the transactivation potential of c-Maf and MafB for the rat gammaD-crystallin Maf-responsive element (gammaD MARE) is dependent upon the cellular context and, using chimeric and single domain mutants, that c-Maf is most likely to be the cognate factor for the gammaD MARE in the lens. Transactivation of the gammaD MARE by c-Maf in lens cells was not enhanced by c-Fos or c-Jun and was not blocked by dominant negative c-Fos or c-Jun constructs. c-Maf can activate the gammaD MARE as a homodimer since activation of the gammaD-crystallin promoter in P19 embryonic carcinoma cells required only c-Maf, but none of a number of c-Fos and c-Jun family members tested. Transactivation by c-Maf was inhibited by activation of protein kinase A (PKA) (by signal transduction agonist forskolin) or of protein kinase C (PKC) (by signal transduction agonist tetradecanoyl phorbol acetate). Site-directed mutagenesis showed that this effect is not mediated by phosphorylation of the consensus PKA/PKC site in the extended DNA-binding domain, but likely involves activation of MAP kinase kinase, as inhibition by PD98059 increased transactivation by c-Maf.

Animals↗
PubMed2005

Correlation between differentiation plasticity and mRNA expression profiling of CD34+-derived CD14- and CD14+ human normal myeloid precursors.

In spite of their apparently restricted differentiation potentiality, hematopoietic precursors are plastic cells able to trans-differentiate from a maturation lineage to another. To better characterize this differentiation plasticity, we purified CD14- and CD14+ myeloid precursors generated by 'in vitro' culture of human CD34+ hematopoietic progenitors. Morphological analysis of the investigated cell populations indicated that, as expected, they consisted of granulocyte and monocyte precursors, respectively. Treatment with differentiation inducers revealed that CD14- cells were bipotent granulo-monocyte precursors, while CD14+ cells appeared univocally committed to a terminal macrophage maturation. Flow cytometry analysis demonstrated that the conversion of granulocyte precursors to the mono-macrophage maturation lineage occurs through a differentiation transition in which the granulocyte-related myeloperoxidase enzyme and the monocyte-specific CD14 antigen are co-expressed. Expression profiling evidenced that the observed trans-differentiation process was accompanied by a remarkable upregulation of the monocyte-related MafB transcription factor.

Antigens, CD34↗
PubMed2006

MicroRNA fingerprints during human megakaryocytopoiesis.

microRNAs are a highly conserved class of noncoding RNAs with important regulatory functions in proliferation, apoptosis, development, and differentiation. To discover novel regulatory pathways during megakaryocytic differentiation, we performed microRNA expression profiling of in vitro-differentiated megakaryocytes derived from CD34(+) hematopoietic progenitors. The main finding was down-regulation of miR-10a, miR-126, miR-106, miR-10b, miR-17 and miR-20. Hypothetically, the down-regulation of microRNAs unblocks target genes involved in differentiation. We confirmed in vitro and in vivo that miR-130a targets the transcription factor MAFB, which is involved in the activation of the GPIIB promoter, a key protein for platelet physiology. In addition, we found that miR-10a expression in differentiated megakaryocytes is inverse to that of HOXA1, and we showed that HOXA1 is a direct target of miR-10a. Finally, we compared the microRNA expression of megakaryoblastic leukemic cell lines with that of in vitro differentiated megakaryocytes and CD34(+) progenitors. This analysis revealed up-regulation of miR-101, miR-126, miR-99a, miR-135, and miR-20. Our data delineate the expression of microRNAs during megakaryocytopoiesis and suggest a regulatory role of microRNAs in this process by targeting megakaryocytic transcription factors.

Antigens, CD34↗