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Biomedical subjects

Hisato Kondoh

Publications and source records attributed to Hisato Kondoh.

10 recordsLinked to original sources
PubMed2003

p53RFP, a p53-inducible RING-finger protein, regulates the stability of p21WAF1.

The mechanisms by which p53 prevents development of cancer are much more complicated than previously thought. Under normal conditions, p53 is involved in cell-cycle arrest, Q1apoptosis, DNA repair, and inhibition of angiogenesis; it also promotes degradation of proteins through transcriptional regulation of certain target genes. Here we report the isolation of a novel transcriptional target of p53, designated p53RFP (p53-inducible RING-finger protein), whose product has E3 ubiquitin ligase activity. Its expression was negatively correlated to that of p21(WAF1) protein; p53RFP is likely to play a role in the regulation of this protein, probably through interaction with, and ubiquitination of, p21(WAF1). p53RFP appears to represent the second known example, the first being MDM2, of an E3 ubiquitin ligase as a p53 target. Our results further suggest that p53 might regulate the stability of p21(WAF1) through transcriptional regulation of p53RFP, and this feature may represent a novel mechanism for a p53-dependent cell-cycle checkpoint.

Amino Acid Sequence↗
PubMed2003

Mice lacking ZFHX1B, the gene that codes for Smad-interacting protein-1, reveal a role for multiple neural crest cell defects in the etiology of Hirschsprung disease-mental retardation syndrome.

Recently, mutations in ZFHX1B, the gene that encodes Smad-interacting protein-1 (SIP1), were found to be implicated in the etiology of a dominant form of Hirschsprung disease-mental retardation syndrome in humans. To clarify the molecular mechanisms underlying the clinical features of SIP1 deficiency, we generated mice that bear a mutation comparable to those found in several human patients. Here, we show that Zfhx1b-knockout mice do not develop postotic vagal neural crest cells, the precursors of the enteric nervous system that is affected in patients with Hirschsprung disease, and they display a delamination arrest of cranial neural crest cells, which form the skeletomuscular elements of the vertebrate head. This suggests that Sip1 is essential for the development of vagal neural crest precursors and the migratory behavior of cranial neural crest in the mouse. Furthermore, we show that Sip1 is involved in the specification of neuroepithelium.

Animals↗
PubMed2003

MEPD: a Medaka gene expression pattern database.

The Medaka Expression Pattern Database (MEPD) stores and integrates information of gene expression during embryonic development of the small freshwater fish Medaka (Oryzias latipes). Expression patterns of genes identified by ESTs are documented by images and by descriptions through parameters such as staining intensity, category and comments and through a comprehensive, hierarchically organized dictionary of anatomical terms. Sequences of the ESTs are available and searchable through BLAST. ESTs in the database are clustered upon entry and have been blasted against public data-bases. The BLAST results are updated regularly, stored within the database and searchable. The MEPD is a project within the Medaka Genome Initiative (MGI) and entries will be interconnected to integrated genomic map databases. MEPD is accessible through the WWW at http://medaka.dsp.jst.go.jp/MEPD.

Animals↗
PubMed2003

Analysis of Wnt8 for neural posteriorizing factor by identifying Frizzled 8c and Frizzled 9 as functional receptors for Wnt8.

The dorsal ectoderm of vertebrate gastrula is first specified into anterior fate by an activation signal and posteriorized by a graded transforming signal, leading to the formation of forebrain, midbrain, hindbrain and spinal cord along the anteroposterior (A-P) axis. Transplanted non-axial mesoderm rather than axial mesoderm has an ability to transform prospective anterior neural tissue into more posterior fates in zebrafish. Wnt8 is a secreted factor that is expressed in non-axial mesoderm. To investigate whether Wnt8 is the neural posteriorizing factor that acts upon neuroectoderm, we first assigned Frizzled 8c and Frizzled 9 to be functional receptors for Wnt8. We then, transplanted non-axial mesoderm into the embryos in which Wnt8 signaling is cell-autonomously blocked by the dominant-negative form of Wnt8 receptors. Non-axial mesodermal transplants in embryos in which Wnt8 signaling is cell-autonomously blocked induced the posterior neural markers as efficiently as in wild-type embryos, suggesting that Wnt8 signaling is not required in neuroectoderm for posteriorization by non-axial mesoderm. Furthermore, Wnt8 signaling, detected by nuclear localization of beta-catenin, was not activated in the posterior neuroectoderm but confined in marginal non-axial mesoderm. Finally, ubiquitous over-expression of Wnt8 does not expand neural ectoderm of posterior character in the absence of mesoderm or Nodal-dependent co-factors. We thus conclude that other factors from non-axial mesoderm may be required for patterning neuroectoderm along the A-P axis.

Amino Acid Sequence↗
PubMed2003

Functional analysis of chicken Sox2 enhancers highlights an array of diverse regulatory elements that are conserved in mammals.

Sox2 expression marks neural and sensory primordia at various stages of development. A 50 kb genomic region of chicken Sox2 was isolated and scanned for enhancer activity utilizing embryo electroporation, resulting in identification of a battery of enhancers. Although Sox2 expression in the early embryonic CNS appears uniform, it is actually pieced together by five separate enhancers with distinct spatio-temporal specificities, including the one activated by the neural induction signals emanating from Hensen's node. Enhancers for Sox2 expression in the lens and nasal/otic placodes and in the neural crest were also determined. These functionally identified Sox2 enhancers exactly correspond to the extragenic sequence blocks conspicuously conserved between chicken and mammals, which are not discernible by sequence comparison among mammals.

Animals↗
PubMed2003

An expression pattern screen for genes involved in the induction of the posterior nervous system of zebrafish.

The posterior nervous system, including the hindbrain and the spinal cord, has been shown to be formed by the transformation of neural plate of anterior character by signals derived from non-axial mesoderm. Although secreted factors, such as fibroblast growth factors (FGFs), Wnts, retinoic acid (RA) and Nodal, have been proposed to be the posteriorizing factors, the mechanism how neural tissue of posterior character is induced and subsequently specified along the anteroposterior axis remains elusive. To identify intercellular signaling molecules responsible for posteriorization of the neural plate as well as to find molecules induced intracellularly by the posteriorizing signal in the caudal neural plate, we screened by in situ hybridization for genes specifically expressed in posterior tissues, including the posterior neural plate and non-axial mesoderm when posteriorization of the neural plate takes place. From a subtracted library differentiating anterior versus posterior neural plate, 420 cDNA clones were tested, out of which 76 cDNA fragments showed expression restricted to the posterior tissue. These clones turned out to represent 32 different genes, including one novel secreted factor and one transmembrane protein. Seven genes were induced by non-axial mesodermal implants and bFGF beads, suggesting that these are among the early-response genes of the posteriorizing signal. Thus, our approach employing cDNA subtraction and subsequent expression pattern screening allows us to clone candidate genes involved in a novel signaling pathway contributing to the formation of the posterior nervous system.

Animals↗
PubMed2002

Wnt signaling plays an essential role in neuronal specification of the dorsal spinal cord.

In the developing spinal cord, signals from the roof plate are required for the development of three classes of dorsal interneuron: D1, D2, and D3, listed from dorsal to ventral. Here, we demonstrate that absence of Wnt1 and Wnt3a, normally expressed in the roof plate, leads to diminished development of D1 and D2 neurons and a compensatory increase in D3 neuron populations. This occurs without significantly altered expression of BMP and related genes in the roof plate. Moreover, Wnt3a protein induces expression of D1 and D2 markers in the isolated medial region of the chick neural plate, and Noggin does not interfere with this induction. Thus, Wnt signaling plays a critical role in the specification of cell types for dorsal interneurons.

Animals↗
PubMed2002

Distinct roles of SOX2, Pax6 and Maf transcription factors in the regulation of lens-specific delta1-crystallin enhancer.

BACKGROUND: The eye lens provides a good model for the study of regulation of cell differentiation, in which lens-specific delta1-crystallin expression serves as an indicator of the differentiated state of the cells. It has been indicated that the SOX2, Pax6 and Maf proteins are the major regulators of lens cell differentiation. To clarify the individual roles of these transcription factors, we analysed their participation in regulation of the delta1-crystallin enhancer. RESULTS: We defined the major binding sites of SOX2, Pax6 and Maf transcription factors in the delta1-crystallin enhancer and assessed the effect of mutations at these sites in the cultured lens epithelial cells and in developing lenses of transgenic mouse embryos. SOX2 (or SOX1/SOX3) is essential for activation of the enhancer under all conditions. Pax6 bound at the deltaEF3 site is required for activation of the enhancer, while Pax6 at the Pax6U site appears to be involved in the Pax6-dependent suppression of the enhancer. In contrast, Maf proteins are only required for high enhancer activity in lens fibre cells. CONCLUSION: The distinct roles of these transcription factors in the regulation of delta1-crystallin enhancer would tend to indicate their individual functions in lens differentiation. The activity of SOX2 and the related SOX1/3 is essential at all stages of lens development as transcriptional activators. Pax6, although it is required in all steps, probably exerts complex regulatory effects, since it possesses both the potential to activate and repress. The major function of Maf proteins presumably resides in the activation of the genes in lens fibre cells.

Animals↗
PubMed2002

Six3-mediated auto repression and eye development requires its interaction with members of the Groucho-related family of co-repressors.

Recent findings suggest that Six3, a member of the evolutionarily conserved So/Six homeodomain family, plays an important role in vertebrate visual system development. However, little is known about the molecular mechanisms by which this function is accomplished. Although several members of the So/Six gene family interact with members of the eyes absent (Eya) gene family and function as transcriptional activators, Six3 does not interact with any known member of the Eya family. Here, we report that Grg4 and Grg5, mouse counterparts of the Drosophila transcriptional co-repressor Groucho, interact with mouse Six3 and its closely related member Six6, which may also be involved in vertebrate eye development. The specificity of the interaction was validated by co-immunoprecipitation of Six3 and Grg4 complexes from cell lines. We also show that the interaction between Six3 and Grg5 requires the Q domain of Grg5 and a conserved phenylalanine residue present in an eh1-like motif located in the Six domain of Six3. The pattern of Grg5 expression in the mouse ventral forebrain and developing optic vesicles overlapped that previously reported for Six3 and Six6. Using PCR, we identified a specific DNA motif that is bound by Six3 and we demonstrated that Six3 acts as a potent transcriptional repressor upon its interaction with Groucho-related members. We also demonstrated that this interaction is required for Six3 auto repression. The biological significance of this interaction in the retina and lens was assessed by overexpression experiments using either wild type full-length Six3 cDNA or a mutated form of this gene in which the interaction with Groucho proteins was disrupted. Overexpression of wild type Six3 by in vivo retroviral infection of newborn rat retinae led to an altered photoreceptor phenotype, while the in ovo electroporation of chicken embryos resulted in failure of lens placode invagination and production of delta-crystallin-negative cells within the placode. These specific alterations were not seen when the mutated form of Six3 cDNA was used in similar experimental approaches, indicating that Six3 interaction with Groucho proteins plays an essential role in vertebrate eye development.

Amino Acid Motifs↗