Biomedical subjects

Noriyuki Kishi

Publications and source records attributed to Noriyuki Kishi.

3 recordsLinked to original sources

PubMed2005

Dissecting MECP2 function in the central nervous system.

Rett syndrome is a neurodevelopmental disorder and an important cause of mental retardation and autistic behavior in girls and in a small group of boys. In 1999, mutation of the methyl-CpG binding protein 2 (MECP2) gene encoding a transcriptional repressor on the X chromosome was found to cause Rett syndrome. Since this discovery, significant research has focused on the elucidation of its specific role in the central nervous system. Recent studies revealed that MECP2 is expressed in more differentiated neurons rather than in less differentiated neuroblasts and that MECP2 is involved in the maturation and maintenance of neurons, including dendritic arborization and axonal projections, rather than in early cell fate decisions in the mammalian brain. In this review, we summarize recent findings regarding regional, temporal, and cell type-specific MECP2 expression in the central nervous system; neurobiologic abnormalities in MECP2 -mutant mice; and MECP2 target genes in the central nervous system.

Animals↗

PubMed2004

MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions.

Rett syndrome is a neurodevelopmental disorder and one of the causes of mental retardation and autistic behavior in girls, as well as in a small group of boys. It was recently discovered that mutation of the methyl-CpG-binding protein 2 (MECP2) gene encoding a transcriptional repressor on the X chromosome causes Rett syndrome. Although it is evident that phenotypes of MECP2 mutant mice that resemble those of Rett syndrome are attributable to lack of the MECP2 gene in the central nervous system (CNS), there is little understanding of the neuropathological abnormalities in the CNS of MECP2-null mice. Here, we investigated the developmental regulation and specific cellular expression of MECP2 during neural development both in vitro and in vivo. MECP2 is expressed in mature neurons, but not in astroglia or oligodendroglia, and is increasingly expressed during development of the mouse neocortex. In addition, in vitro culture studies suggest that MECP2 is expressed in more differentiated neurons rather than in less differentiated neuroblasts. Under in vitro conditions using neural precursor cultures, we find that MECP2 mutant neural precursors differentiate into morphologically mature neurons and glia, and no significant differences in differentiation are detected between cells from wild-type and MECP2 mutant mice, suggesting that MECP2 may play a different role in mice than it does in Xenopus embryos. In agreement with this hypothesis, neocortical projection layers in MECP2 -/y mice are thinner than those in wild-type mice, and pyramidal neurons in layer II/III in MECP2 -/y mice are smaller and less complex than those in wild-type mice. Taken together, our results indicate that MECP2 is involved in the maturation and maintenance of neurons, including dendritic arborization, rather than in cell fate decisions.

Animals↗

PubMed2002

Involvement of a proline-rich motif and RING-H2 finger of Deltex in the regulation of Notch signaling.

The Notch pathway is an evolutionarily conserved signaling mechanism that is essential for cell-cell interactions. The Drosophila deltex gene regulates Notch signaling in a positive manner, and its gene product physically interacts with the intracellular domain of Notch through its N-terminal domain. Deltex has two other domains that are presumably involved in protein-protein interactions: a proline-rich motif that binds to SH3-domains, and a RING-H2 finger motif. Using an overexpression assay, we have analyzed the functional involvement of these Deltex domains in Notch signaling. The N-terminal domain of Deltex that binds to the CDC10/Ankyrin repeats of the Notch intracellular domain was indispensable for the function of Deltex. A mutant form of Deltex that lacked the proline-rich motif behaved as a dominant-negative form. This dominant-negative Deltex inhibited Notch signaling upstream of an activated, nuclear form of Notch and downstream of full-length Notch, suggesting the dominant-negative Deltex might prevent the activation of the Notch receptor. We found that Deltex formed a homo-multimer, and mutations in the RING-H2 finger domain abolished this oligomerization. The same mutations in the RING-H2 finger motif of Deltex disrupted the function of Deltex in vivo. However, when the same mutant was fused to a heterologous dimerization domain (Glutathione-S-Transferase), the chimeric protein had normal Deltex activity. Therefore, oligomerization mediated by the RING-H2 finger motif is an integral step in the signaling function of Deltex.

Amino Acid Motifs↗