Premature thelarche caused by plant growth factors.
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Breast↗
Biomedical subjects
E Bober
Publications and source records attributed to E Bober.
Five Nkx5 genes show differential expression patterns in anlagen of sensory organs in medaka: insight into the evolution of the gene family.
We report the identification and characterisation of five different Nkx5-related genes in medaka fish (Oryzias latipes). They constitute homologues of genes previously isolated in higher vertebrates, Nkx5--1, Nkx5--2, Hmx1/Nkx5--3 and SOHo-1, and were named accordingly: OlNkx5--1.1, OlNkx5--2, OlNkx5--3 and OlSOHo. For the Nkx5--1 gene a new, second homologue, OlNkx5--1.2, was isolated. In medaka, Nkx5 and SOHo genes are differentially expressed in three developing sensory organs: eye, ear and lateral line and later in defined brain regions. Phylogenetic analyses of the entire Nkx5 family revealed that four paralogous Nkx5 groups, Nkx5--1, Nkx5--2, Hmx1/Nkx5--3/GH6 and SOHo, are present in vertebrates. Only some of the Nkx5 family members have been identified in singular vertebrate species so far. Here we present, for the first time, the isolation of representatives of each Nkx5 subgroup in one species, the medaka fish. Based on similarities in sequence and expression patterns, and genomic organisation we propose a model of the evolutionary history of the Nkx5 family. The model predicts that the four vertebrate Nkx5 genes arose by a tandem duplication, followed by chromosomal duplication. The two Nkx5--1 genes identified so far exclusively in medaka most probably result from an additional genome duplication in the fish lineage.
Amino Acid Sequence↗
FGFs control the patterning of the inner ear but are not able to induce the full ear program.
FGF2 or FGF8 applied ectopically, close to the developing otic placode enhances transcription of a subset of ear marker genes such as Nkx5-1, SOHo1 and Pax2. Other ear expressed genes (Dlx5 and BMP4) are not up-regulated by FGFs. Ectopic FGFs lead to an increase in size of the vestibulo-cochlear ganglion. This phenotypic change is due to an increased recruitment of epithelial cells to the neuronal fate rather than to an enhanced proliferation. We also observed an induction of additional, vesicle-like structures upon ectopic FGF treatment, but this induction never led to enrolment of a full ear program. We further demonstrate that FGF8 is expressed in two separate, short waves, first at the otic placode stage and later at the vesicle stage. Both activities correspond to critical morphogenetic events in ear development. We propose that FGF8 is an important regulator of otocyst patterning.
Animals↗
Development of the vertebrate inner ear.
The inner ear, also called the membranous labyrinth, contains the cochlea, which is responsible for the sense of hearing, and the vestibular apparatus, which is necessary for the sense of balance and gravity. The inner ear arises in the embryo from placodes, which are epithelial thickenings of the cranial ectoderm symmetrically located on either side of hindbrain rhombomeres 5 and 6. Placode formation in mice is first visible at the 12-somite stage and is controlled by surrounding tissues, the paraxial mesoderm and neural ectoderm. Diffusible molecules such as growth factors play an important role in this process. The activity of several genes confers the identity to the placodal cells. Subsequent cellular proliferation processes under influences from the adjacent hindbrain cause the inner ear epithelium to invaginate and form a vesicle called the otocyst. Combinatorial expression of several genes and diffusible factors secreted from the vesicle epithelium and hindbrain control specification of distinct inner ear compartments. Transplantation studies and inner ear in vitro cultures show that each of these compartments is already committed to develop unique inner ear structures. Later developmental periods are principally characterized by intrinsic differentiation processes. In particular, sensory patches differentiate into fully functional sensory epithelia, and the semicircular canals along with the cochlear duct are elaborated and ossified.
Animals↗
Inner ear and lateral line expression of a zebrafish Nkx5-1 gene and its downregulation in the ears of FGF8 mutant, ace.
An orthologue of the mouse homeobox gene Nkx5-1 was cloned and characterized in the zebrafish. As in the mouse and chick, the zebrafish Nkx5-1 gene is expressed in the ear placode and vesicle and in cells forming the vestibulo-acoustic ganglion. In addition, a novel expression domain, the lateral line, appears in the zebrafish, supporting a common precursor hypothesis for these two organs. In the FGF8 zebrafish mutant ace, expression of Nkx5-1 in the otic structures is diminished. The most significant reduction of zfNkx5-1 expression was observed in cells of the vestibulo-acoustic ganglion.
Amino Acid Sequence↗
Netrin 1 is required for semicircular canal formation in the mouse inner ear.
The morphogenetic development of the mammalian inner ear is a complex multistep process, the molecular and cellular details of which are only beginning to be unraveled. We show here that mouse netrin 1, known to be involved in axon guidance and cell migration in the central nervous system, also plays a critical morphogenetic role during semicircular canal formation. netrin 1 is expressed at high levels in the otic epithelium, in cells that will come together to form a fusion plate, a prerequisite for the formation of semicircular canals. In netrin 1 mutant mice, fusion plate formation is severely affected resulting in a reduced anterior semicircular canal and the complete lack of the posterior and lateral canals. Our results suggest that netrin 1 facilitates semicircular canal formation through two different mechanisms: (1) it participates in the detachment of the fusion plate epithelia from the basement membrane, and (2) it stimulates proliferation of the periotic mesenchymal cells which then push the epithelial cell walls together to form the fusion plate.
Alleles↗
[Measurement of fluid compartments using electrical bioimpedance for assessment of target weight in hemodialysis patients].
The prescription of optimal hydration status in hemodialysis patients remains a much disputed topic in dialysis treatment. In particular, assessment of the patients optimal weight ("target weight") poses considerable difficulties. Multifrequency bioimpedance spectroscopy analysis (BIS) has been recommended as a non invasive, practical, and relatively non expensive method to determine hydration and nutritional status in patients on maintenance hemodialysis (HD). In the current study we used whole body BIS analysis for determination of body water (BW) compartments; total body water (TBW), extracellular water (ECW), and intracellular water (ICW) in 133 healthy adults, and in 227 hemodialysis patients with end-stage renal disease. BIS results were compared to anthropometric measurements. Our results showed strong correlation between TBW measured by BIS in control group in comparison to anthropometric calculation (p = 0.001). In HD patients we observed higher range of TBW, and TBW/ECW ratio (from 15.6 to 56.1 L and from 0.33 to 0.78), as measured by BIS at pre-HD, and also post-HD period (TBW ranged from 13.1 to 56.2 L, ECW/TBW ratio ranged from 0.33 to 1.27). The TBW BIS results did not correlate with anthropometric calculation. We postulate using of multi-frequency bioimpedance technique in precise determination of fluid compartments and in consequence in the assessment of "target weight" in hemodialysis population.
Adult↗
Craniofacial, vestibular and bone defects in mice lacking the Distal-less-related gene Dlx5.
The Dlx5 gene encodes a Distal-less-related DNA-binding homeobox protein first expressed during early embryonic development in anterior regions of the mouse embryo. In later developmental stages, it appears in the branchial arches, the otic and olfactory placodes and their derivatives, in restricted brain regions, in all extending appendages and in all developing bones. We have created a null allele of the mouse Dlx5 gene by replacing exons I and II with the E. coli lacZ gene. Heterozygous mice appear normal. Beta-galactosidase activity in Dlx5+/- embryos and newborn animals reproduces the known pattern of expression of the gene. Homozygous mutants die shortly after birth with a swollen abdomen. They present a complex phenotype characterised by craniofacial abnormalities affecting derivatives of the first four branchial arches, severe malformations of the vestibular organ, a delayed ossification of the roof of the skull and abnormal osteogenesis. No obvious defect was observed in the patterning of limbs and other appendages. The defects observed in Dlx5-/- mutant animals suggest multiple and independent roles of this gene in the patterning of the branchial arches, in the morphogenesis of the vestibular organ and in osteoblast differentiation.
Animals↗
Two highly related homeodomain proteins, Nkx5-1 and Nkx5-2, display different DNA binding specificities.
The mouse Nkx5-1 and Nkx5-2 genes are related to NK genes in Drosophila and encode proteins with very similar homeodomains. In higher vertebrates Nkx5 genes are specifically expressed in the inner ear. Inactivation of the mouse Nkx5-1 gene by homologous recombination revealed a critical role for the formation of vestibular inner ear structures. Here, we investigated biochemical properties of the proteins encoded by the Nkx5 genes. A similar consensus binding sequence was isolated for both Nkx5 proteins using binding site selection. This sequence is related to target sequences previously identified for other Nkx proteins and contains the conserved homeodomain binding core TAAT. An additional, novel and unrelated high affinity binding sequence could be identified for the Nkx5-2 protein.
Amino Acid Sequence↗
Nkx5-1 controls semicircular canal formation in the mouse inner ear.
The inner ear develops from the otic vesicle, a one-cell-thick epithelium, which eventually transforms into highly complex structures including the sensory organs for balance (vestibulum) and hearing (cochlea). Several mouse inner ear mutations with hearing and balance defects have been described but for most the underlying genes have not been identified, for example, the genes controlling the development of the vestibular organs. Here, we report the inactivation of the homeobox gene, Nkx5-1, by homologous recombination in mice. This gene is expressed in vestibular structures throughout inner ear development. Mice carrying the Nkx5-1 null mutation exhibit behavioural abnormalities that resemble the typical hyperactivity and circling movements of the shaker/waltzer type mutants. The balance defect correlates with severe malformations of the vestibular organ in Nkx5-1(-/-) mutants, which fail to develop the semicircular canals. Nkx5-1 is the first ear-specific molecule identified to play a crucial role in the formation of the mammalian vestibular system.
Animals↗
Two regulatory genes, cNkx5-1 and cPax2, show different responses to local signals during otic placode and vesicle formation in the chick embryo.
The early stages of otic placode development depend on signals from neighbouring tissues including the hindbrain. The identity of these signals and of the responding placodal genes, however, is not known. We have identified a chick homeobox gene cNkx5-1, which is expressed in the otic placode beginning at stage 10 and exhibits a dynamic expression pattern during formation and further differentiation of the otic vesicle. In a series of heterotopic transplantation experiments, we demonstrate that cNkx5-1 can be activated in ectopic positions. However, significant differences in otic development and cNkx5-1 gene activity were observed when placodes were transplanted into the more rostral positions within the head mesenchyme or into the wing buds of older hosts. These results indicate that only the rostral tissues were able to induce and/or maintain ear development. Ectopically induced cNkx5-1 expression always reproduced the endogenous pattern within the lateral wall of the otocyst that is destined to form vestibular structures. In contrast, cPax2 which is expressed in the medial wall of the early otic vesicle later forming the cochlea never resumed its correct expression pattern after transplantation. Our experiments illustrate that only some aspects of gene expression and presumably pattern formation during inner ear development can be established and maintained ectopically. In particular, the dorsal vestibular structures seem to be programmed earlier and differently from the ventral cochlear part.
Animals↗
Regionalized expression of Nkx5-1, Nkx5-2, Pax2 and sek genes during mouse inner ear development.
Nkx5-1 and Nkx5-2 are two highly related homeobox genes which are expressed during mouse development in the inner ear. Here, we present the detailed expression of both genes within the developing ear and a comparison to the expression of other potential control genes in this organ. Both genes are active between E13.5 and birth in non-sensory epithelium of the semicircular canals, utricle and saccule. Nkx5-1 and Nkx5-2 are also expressed in the cochlea, where the expression is restricted to the stria vascularis. The endolymphatic duct is devoid of any Nkx5 transcripts. Pax2 is expressed in epithelial cells of the ventral part of the membranous labyrinth where it overlaps with the Nkx5 expression domain. sek shows a complementary pattern to Nkx5 in the vestibular epithelium. In the cochlea sek is expressed throughout the mesenchyme and epithelium but not in the stria vascularis. In the vestibulum Pax2 and sek is limited to the ventral part whereas Nkx5 genes are active throughout. These data suggest that Nkx5 genes, Pax2 and sek play different roles in the patterning of inner ear structures.
Animals↗
Picture of the month. Transient primary hypothyroidism.
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Humans↗
Gene targeting the myf-5 locus with nlacZ reveals expression of this myogenic factor in mature skeletal muscle fibres as well as early embryonic muscle.
We have introduced the nlacZ reporter gene into the locus of the myogenic factor gene myf-5 by homologous recombination in embryonic stem (ES) cells. Targeted ES clones were injected into precompaction morula, and the beta-galactosidase expression pattern was monitored. These mice permit the sensitive visualization of myf-5 expression throughout the embryo, and provide a standard for comparing it with that seen with different myf-5/nlacZ transgenes. Thus, in a comparison using ES cells in chimaeric embryos containing the targeted or randomly integrated myf-5/nlacZ construct, we demonstrate that 5.5 kbp of myf-5 upstream flanking sequence including exon1 and most of intron1 directs some skeletal muscle expression, but this is neither qualitatively nor quantitatively equivalent to that of the endogenous gene. Myf-5 is expressed early, before terminal myogenesis takes place in the medial half of the somite, and subsequently it is a major myogenic factor as skeletal muscle forms. All skeletal muscle shows beta-galactosidase activity, even after birth, indicating that myf-5 expression is not confined to primary myotubes, which are derived from embryonic myoblasts, but is also present in muscles containing different adult fibre types. The presence of myf-5 transcripts from the endogenous gene in older muscle was confirmed by in situ hybridization. These results suggest that the myf-5 gene is not activated in only a subset of muscle cells and are consistent with the results on the MyoD knockout mice.
Animals↗
Distinct temporal expression of mouse Nkx-5.1 and Nkx-5.2 homeobox genes during brain and ear development.
The mouse Nkx-5.1 and Nkx-5.2 genes have been identified by sequence homology to Drosophila NK genes within the homeobox domain. Here, we report the isolation of the Nkx-5.2 cDNA and a detailed comparative analysis of the spatio-temporal expression patterns for Nkx-5.1 and Nkx-5.2 genes. Nkx-5.2 transcripts are first detected in E13.5 embryos where they colocalize with Nkx-5.1 mRNA in the developing central nervous system and the inner ear. However, the onset of Nkx-5.1 transcription begins much earlier in 10 somite stage embryos (E8.5) in the otic placode and the branchial region. Nkx-5.1 expression in the ear persists until birth, whereas in branchial arches it is transient between E8.5 to E11.5. Transcript distribution appears regionalized in the otic vesicle concentrating at the anterior and posterior margin and later at the dorsal side of the otocyst. These domains are distinct from regions expressing Pax-2 and sek, two other early markers for otic development. From E11.5 to birth several Nkx-5.1 expression domains appear in the brain between the ventral diencephalon and the myelencephalon. The same expression domains also exist for Nkx-5.2 beginning at E13.5. The regionally restricted expression pattern of both Nkx-5 genes during mouse development suggests their involvement in cell type specification of neuronal cells.
Animals↗
Early skeletal muscle development proceeds normally in parthenogenetic mouse embryos.
In mouse chimeras with parthenogenetic cell contribution, the skeletal musculature appears to be largely devoid of parthenogenetically derived cells. To analyze the appearance and early distribution of myotomal cells in parthenotes, we determined the expression of the muscle-specific transcription factors myogenin, MYF-5, and MYF-6 by in situ hybridization in somites of Day 10 and 11 embryos. Here, we report that these myogenic regulatory proteins are expressed in parthenogenetic animals together with desmin, one of the early muscle-specific structural proteins. We also show that parthenogenetic cells contribute equally to dermatome, sclerotome, and myotome in Day 10 and 11 chimeras. These results suggest that early myotomal cells expressing the myogenic control proteins develop and allocate normally in parthenogenetic embryos and in parthenogenetic<==>normal chimeras. The underrepresentation in older chimeras may therefore be due to selective elimination. These data also argue against imprinting of the myogenic factor genes myogenin, Myf-5, and Myf-6.
Animals↗
A novel NK-related mouse homeobox gene: expression in central and peripheral nervous structures during embryonic development.
We have identified three novel mouse homeobox genes that are related to the Drosophila NK gene family. Two genes without direct homologues in Drosophila were designated Nkx-5.1 and Nkx-5.2; the third gene Nkx-1.1 constitutes the mouse homologue to NK1.Nkx-5.1 and Nkx-5.2 are closely linked on mouse chromosome 7, whereas Nkx-1.1 is located on a different chromosome. Here, we report the spatiotemporal expression pattern of Nkx-5.1 during prenatal mouse development. Nkx-5.1 gene activity begins at Embryonic Day 10.5 in the developing ear, the neural tube, and dorsal root ganglia. It continues to be active throughout prenatal life in discrete regions of the brain with an anterior border in the ventral diencephalon at the optic chiasma and expression domains in mesencephalon, metencephalon, and myelencephalon. At midgestation, Nkx-5.1 is also expressed in mesenchyme of the head and branchial arches, and in some cranial ganglia, as well as in derivatives of neural crest, such as the truncus sympathicus and myenteric ganglia. The time pattern of Nkx-5.1 expression and its confinement to primarily postmitotic cells of the central and peripheral nervous system suggest that Nkx-5.1 may play a role in the specification of neuronal cell types.
Amino Acid Sequence↗
Muscle cell differentiation of embryonic stem cells reflects myogenesis in vivo: developmentally regulated expression of myogenic determination genes and functional expression of ionic currents.
The mouse blastocyst-derived embryonic stem cell (ES cell) line BLC6 efficiently differentiates into myosin heavy chain-, desmin- and myogenin-positive skeletal muscle cells when cultivated in embryo-like aggregates (embryoid bodies). Here, we show that the muscle-specific determination genes myf5, myogenin, myoD, and myf6 are expressed in these embryoid bodies in a characteristic temporal pattern which precisely reflects the sequence observed during mouse development in vivo. Myf5 is the first gene to be expressed followed by myogenin, myoD, and myf6, in this order. In situ hybridization demonstrates transcripts for myogenin and myoD accumulating in mono- and multinucleated myogenic cells, while myf5 mRNA is already found in mononucleated myoblasts. The myocytes also express functional nicotinic cholinoceptors and exhibit T-type Ca2+ currents and later L-type Ca2+ currents, demonstrating physiological properties of skeletal muscle cells. During myocyte differentiation the density of L-type Ca2+ channels significantly increases while the density of T-type Ca2+ channels decreases. The effect of external signals on myogenic differentiation of BLC6 cells was demonstrated by cocultivation with visceral endodermal END-2 cells and the activin A-secreting WEHI-3 cells. END-2 cells essentially prevent skeletal muscle differentiation, whereas basic fibroblast growth factor, transforming growth factor-beta, and WEHI-3 cells have no or an attenuating effect, respectively. Our results suggest that ES cells recapitulate closely the early steps of muscle development in vivo and may serve as an excellent in vitro system to study this process.
Animals↗