[Mechanism of neural stem cell fate specification].
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Acetylation↗
Biomedical subjects
Kinichi Nakashima
Publications and source records attributed to Kinichi Nakashima.
Enhanced gene activation by Notch and BMP signaling cross-talk.
The signaling systems of Notch and bone morphogenetic protein (BMP) are highly conserved from flies to mammals and have been shown to be important in the development of multiple organs. For instance, in the fate determination of mouse neuroepithelial cells, Notch signaling plays a role in keeping the progenitors from differentiating into neurons. BMP is also known to inhibit neuronal differentiation. In this paper, we show that BMP2 enhances Notch-induced transcriptional activation of Hes-5 and Hesr-1 in mouse neuroepithelial cells. BMP2 stimulation, in addition to the introduction of the intracellular domain of Notch (NIC), resulted in enhanced activation of the Hes-5 gene promoter. RBP-Jkappa binding to its target sequence is important not only for Notch signaling, but also for BMP2 signaling, to activate the Hes-5 gene promoter. Smad1, a Smad species that is activated by BMP2, barely interacted with NIC, but did form a complex with NIC in the simultaneous presence of the coactivators P/CAF and p300. Recruitment of p300 to the NIC-containing complex was facilitated by activated Smad1, which is suggested to contribute to BMP2-mediated enhancement of Notch-induced Hes-5 expression. These data suggest a novel functional cooperation between Notch signaling and BMP signaling.
Acetyltransferases↗
Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function.
DNA methylation-mediated epigenetic regulation plays critical roles in regulating mammalian gene expression, but its role in normal brain function is not clear. Methyl-CpG binding protein 1 (MBD1), a member of the methylated DNA-binding protein family, has been shown to bind methylated gene promoters and facilitate transcriptional repression in vitro. Here we report the generation and analysis of MBD1-/- mice. MBD1-/- mice had no detectable developmental defects and appeared healthy throughout life. However, we found that MBD1-/- neural stem cells exhibited reduced neuronal differentiation and increased genomic instability. Furthermore, adult MBD1-/- mice had decreased neurogenesis, impaired spatial learning, and a significant reduction in long-term potentiation in the dentate gyrus of the hippocampus. Our findings indicate that DNA methylation is important in maintaining cellular genomic stability and is crucial for normal neural stem cell and brain functions.
Animals↗
Interisland evolution of Trimeresurus flavoviridis venom phospholipase A(2) isozymes.
Trimeresurus flavoviridis snakes inhabit the southwestern islands of Japan. A phospholipase A(2) (PLA(2)), named PL-Y, was isolated from Okinawa T. flavoviridis venom and its amino acid sequence was determined from both protein and cDNA. PL-Y was unable to induce edema. In contrast, PLA-B, a PLA(2) from Tokunoshima T. flavoviridis venom, which is different at only three positions from PL-Y, is known to induce edema. A new PLA(2), named PLA-B', which is similar to PLA-B, was cloned from Amami-Oshima T. flavoviridis venom gland. Three T. flavoviridis venom basic [Asp(49)]PLA(2) isozymes, PL-Y (Okinawa), PLA-B (Tokunoshima), and PLA-B' (Amami-Oshima), are identical in the N-terminal half but have one to four amino acid substitutions in the beta1-sheet and its vicinity. Such interisland sequence diversities among them are due to isolation in the different environments over 1 to 2 million years and appear to have been brought about by natural selection for point mutation in their genes. Otherwise, a major PLA(2), named PLA2, ubiquitously exists in the venoms of T. flavoviridis snakes from the three islands with one to three synonymous substitutions in their cDNAs. It is assumed that the PLA2 gene is a prototype among T. flavoviridis venom PLA(2) isozyme genes and has hardly undergone nonsynonymous mutation as a principal toxic component. Phylogenetic analysis based on the amino acid sequences revealed that T. flavoviridis PLA(2) isozymes are clearly separated into three groups, PLA2 type, basic [Asp(49)]PLA(2) type, and [Lys(49)]PLA(2) type. Basic [Asp(49)]PLA(2)-type isozymes may manifest their own particular toxic functions different from those of the isozymes of the PLA2 type and [Lys(49)]PLA(2) type.
Amino Acid Sequence↗
Requirement of gp130 signaling for the AGM hematopoiesis.
OBJECTIVE: Definitive hematopoiesis starts in the aorta-gonad-mesonephros (AGM) region during mouse development and remarkably expands in the liver at a later stage of ontogeny. gp130 is a signal transducing receptor component shared by all the IL-6 family cytokines, whose gene ablation in mouse results in the significant reduction in the fetal liver hematopoiesis. The present study aims to evaluate the role of gp130 signaling in the fetal mouse AGM hematopoiesis. METHODS AND MATERIALS: Mouse AGM regions from the wild-type and gp130-deficient mice on embryonic day 11.5 were dissociated and cultured with a mixture of cytokines, including one which activates gp130. Wild-type human gp130 and its mutant constructs were introduced into cultured gp130-deficient AGM cells using retrovirus system. To further analyze gp130 downstream signaling, a dominant-negative mutant of STAT3 was also introduced. RESULTS: The gp130 deficiency in the culture of fetal mouse AGM cells resulted in the failure of the expansion of the c-kit(+), Sca-1(+), and lineage markers(-) population. Such failure was rescued by introduction of a wild-type gp130 expression construct but not its mutant constructs having no ability to activate STAT3. In the normal AGM cell culture, introduction of a dominant-negative form of STAT3 in which Y(705) was changed to phenylalanine suppressed the expansion of hematopoietic cell colonies. CONCLUSION: gp130 plays an indispensable role in the expansion of hematopoietic precursor cells in the fetal mouse AGM. In particular, the activation of STAT3 by gp130 is found to be important in this process.
Animals↗
Involvement of Oct3/4 in the enhancement of neuronal differentiation of ES cells in neurogenesis-inducing cultures.
Oct3/4 plays a critical role in maintaining embryonic stem cell pluripotency. Regulatable transgene-mediated sustained Oct3/4 expression in ES cells cultured in serum-free LIF-deficient medium caused accelerated differentiation to neuroectoderm-like cells that expressed Sox2, Otx1 and Emx2 and subsequently differentiated into neurons. Neurogenesis of ES cells is promoted by SDIA (stromal cell-derived inducing activity), which accumulates on the PA6 stromal cell surface. Oct3/4 expression in ES cells was maintained by SDIA whereas without it expression was promptly downregulated. Suppression of Oct3/4 abolished neuronal differentiation even after stimulation by SDIA. In contrast, sustained upregulated Oct3/4 expression enhanced SDIA-mediated neurogenesis of ES cells. Therefore, Oct3/4 appears to promote neuroectoderm formation and subsequent neuronal differentiation from ES cells.
Animals↗
The Role of gp130 in cerebral cortical development: in vivo functional analysis in a mouse exo utero system.
The role of gp130 in cerebral cortical histogenesis remains unknown. Mice lacking gp130 showed a hypoplastic cortical plate and decreased incorporation of 5-bromo-2'-deoxyuridine (BrdU) in progenitor cells of the developing cerebrum. In contrast, injection of leukemia inhibitory factor (LIF), a gp130 ligand, into the lateral cerebral ventricle of wild-type embryos exo utero induced hyperplasia of the cerebral cortex and increased the incorporation of BrdU in progenitor cells. Furthermore, chronologically controlled injection of LIF followed or preceded by BrdU revealed that gp130-mediated signals promote the progenitor cells to reenter the stem cell cycle without affecting the duration of cell cycle and enhance the migration of postmitotic neurons in the developing cerebrum.
Animals↗
Cardiotrophin-like cytokine induces astrocyte differentiation of fetal neuroepithelial cells via activation of STAT3.
Cardiotrophin-like cytokine (CLC), also known as novel neurotrophin-1/B cell stimulating factor-3 (NNT-1/BSF-3), is a recently identified member of the interleukin (IL)-6 family of cytokines that share gp130 as a signal-transducing receptor component. In this study, we demonstrate that CLC is expressed in fetal mouse neuroepithelial cells and has a potential to induce their astrocyte differentiation in a synergistic manner with bone-morphogenetic protein (BMP)-2, which is also expressed in the fetal mouse brain. CLC-stimulation led to promoter activation of the gene for an astrocyte marker, glial fibrillary acidic protein (GFAP), which was clearly inhibited by expression of a dominant negative form of a transcription factor, STAT3, or by introduction of a mutation in a single STAT3-binding site in the promoter, suggesting a critical role of STAT3 in the CLC-induced GFAP transcription. These results suggest that CLC plays a role in astrocyte differentiation via STAT3 activation within the developing brain.
Animals↗
Mechanisms underlying cytokine-mediated cell-fate regulation in the nervous system.
Neurons, astrocytes, and oligodendrocytes, the three major cell types in the nervous system, are generated from common neural stem cells during development. Recent studies have provided evidence that neural stem cells are preserved in the adult brain, where, until recently, neurogenesis had not been considered to take place. The mechanisms that gOvern the fate of neural stem-cell determination have yet to be clarified. It is becoming apparent that soluble protein mediators referred to as cytokines play critical roles in cell-fate determination. For instance, bone morphogenetic proteins (BMPs) alter the fate of developing brain cells from a neurogenic differentiation to an astrocytic one. Different types of cytokines sometimes cooperate to modulate differentiation. For example, the interleukin-6 (IL-6) family cytokines and the BMP family cytokines act in synergy to elaborate astrocyte differentiation. In this review, we focus on recent progress that addresses the molecular mechanisms whereby cytokines regulate the fate of cells in neural lineages. We also discuss possible clinical applications of these findings to minimize the undesirable gliogenesis that occurs after neural stem-cell implantation and nerve injury.
Animals↗