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1.  A nonclassical vitamin D receptor pathway suppresses renal fibrosis 
The Journal of Clinical Investigation  2013;123(11):4579-4594.
The TGF-β superfamily comprises pleiotropic cytokines that regulate SMAD and non-SMAD signaling. TGF-β–SMAD signal transduction is known to be involved in tissue fibrosis, including renal fibrosis. Here, we found that 1,25-dihydroxyvitamin D3–bound [1,25(OH)2D3-bound] vitamin D receptor (VDR) specifically inhibits TGF-β–SMAD signal transduction through direct interaction with SMAD3. In mouse models of tissue fibrosis, 1,25(OH)2D3 treatment prevented renal fibrosis through the suppression of TGF-β–SMAD signal transduction. Based on the structure of the VDR-ligand complex, we generated 2 synthetic ligands. These ligands selectively inhibited TGF-β–SMAD signal transduction without activating VDR-mediated transcription and significantly attenuated renal fibrosis in mice. These results indicate that 1,25(OH)2D3-dependent suppression of TGF-β–SMAD signal transduction is independent of VDR-mediated transcriptional activity. In addition, these ligands did not cause hypercalcemia resulting from stimulation of the transcriptional activity of the VDR. Thus, our study provides a new strategy for generating chemical compounds that specifically inhibit TGF-β–SMAD signal transduction. Since TGF-β–SMAD signal transduction is reportedly involved in several disorders, our results will aid in the development of new drugs that do not cause detectable adverse effects, such as hypercalcemia.
PMCID: PMC3809783  PMID: 24135137
3.  Spine Formation Pattern of Adult-Born Neurons Is Differentially Modulated by the Induction Timing and Location of Hippocampal Plasticity 
PLoS ONE  2012;7(9):e45270.
In the adult hippocampus dentate gyrus (DG), newly born neurons are functionally integrated into existing circuits and play important roles in hippocampus-dependent memory. However, it remains unclear how neural plasticity regulates the integration pattern of new neurons into preexisting circuits. Because dendritic spines are major postsynaptic sites for excitatory inputs, spines of new neurons were visualized by retrovirus-mediated labeling to evaluate integration. Long-term potentiation (LTP) was induced at 12, 16, or 21 days postinfection (dpi), at which time new neurons have no, few, or many spines, respectively. The spine expression patterns were investigated at one or two weeks after LTP induction. Induction at 12 dpi increased later spinogenesis, although the new neurons at 12 dpi didn’t respond to the stimulus for LTP induction. Induction at 21 dpi transiently mediated spine enlargement. Surprisingly, LTP induction at 16 dpi reduced the spine density of new neurons. All LTP-mediated changes specifically appeared within the LTP–induced layer. Therefore, neural plasticity differentially regulates the integration of new neurons into the activated circuit, dependent on their developmental stage. Consequently, new neurons at different developmental stages may play distinct roles in processing the acquired information by modulating the connectivity of activated circuits via their integration.
PMCID: PMC3443223  PMID: 23024813
4.  Hippocampal function is not required for the precision of remote place memory 
Molecular Brain  2012;5:5.
During permanent memory formation, recall of acquired place memories initially depends on the hippocampus and eventually become hippocampus-independent with time. It has been suggested that the quality of original place memories also transforms from a precise form to a less precise form with similar time course. The question arises of whether the quality of original place memories is determined by brain regions on which the memory depends.
To directly test this idea, we introduced a new procedure: a non-associative place recognition memory test in mice. Combined with genetic and pharmacological approaches, our analyses revealed that place memory is precisely maintained for 28 days, although the recall of place memory shifts from hippocampus-dependent to hippocampus-independent with time. Moreover, the inactivation of the hippocampal function does not inhibit the precision of remote place memory.
These results indicate that the quality of place memories is not determined by brain regions on which the memory depends.
PMCID: PMC3317849  PMID: 22296713
5.  The E3 Ubiquitin Ligase Activity of Trip12 Is Essential for Mouse Embryogenesis 
PLoS ONE  2011;6(10):e25871.
Protein ubiquitination is a post-translational protein modification that regulates many biological conditions [1], [2], [3], [4]. Trip12 is a HECT-type E3 ubiquitin ligase that ubiquitinates ARF and APP-BP1 [5], [6]. However, the significance of Trip12 in vivo is largely unknown. Here we show that the ubiquitin ligase activity of Trip12 is indispensable for mouse embryogenesis. A homozygous mutation in Trip12 (Trip12mt/mt) that disrupts the ubiquitin ligase activity resulted in embryonic lethality in the middle stage of development. Trip12mt/mt embryos exhibited growth arrest and increased expression of the negative cell cycle regulator p16 [7], [8], [9], [10]. In contrast, Trip12mt/mt ES cells were viable. They had decreased proliferation, but maintained both the undifferentiated state and the ability to differentiate. Trip12mt/mt ES cells had increased levels of the BAF57 protein (a component of the SWI/SNF chromatin remodeling complex) and altered gene expression patterns. These data suggest that Trip12 is involved in global gene expression and plays an important role in mouse development.
PMCID: PMC3196520  PMID: 22028794
6.  LTP induction within a narrow critical period of immature stages enhances the survival of newly generated neurons in the adult rat dentate gyrus 
Molecular Brain  2010;3:13.
Neurogenesis occurs in the adult hippocampus of various animal species. A substantial fraction of newly generated neurons die before they mature, and the survival rate of new neurons are regulated in an experience-dependent manner. Previous study showed that high-frequency stimulation (HFS) of perforant path fibers to the hippocampal dentate gyrus (DG) induces the long-term potentiation (LTP) in the DG, and enhances the survival of newly generated neurons in the DG. In this study, we addressed whether a time period exists during which the survival of new neurons is maximally sensitive to the HFS. We found that the enhancement of cell survival by HFS was exclusively restricted to the specific narrow period during immature stages of new neurons (7-10 days after birth). Furthermore, the pharmacological blockade of LTP induction suppressed the enhancement of cell survival by the HFS. These results suggest that the LTP induction within a narrow critical period of immature stages enhances the survival of newly generated neurons in rat DG.
PMCID: PMC2868842  PMID: 20426820
7.  Decreased postnatal neurogenesis in the hippocampus combined with stress experience during adolescence is accompanied by an enhanced incidence of behavioral pathologies in adult mice 
Molecular Brain  2008;1:22.
Adolescence is a vulnerable period in that stress experienced during this time can affect the incidence of psychiatric disorders later, during adulthood. Neurogenesis is known to be involved in the postnatal development of the brain, but its role in determining an individual's biological vulnerability to the onset of psychiatric disorders has not been addressed.
We examined the role of postnatal neurogenesis during adolescence, a period between 3 to 8 weeks of age in rodents. Mice were X-irradiated at 4 weeks of age, to inhibit postnatal neurogenesis in the sub-granule cell layer of the hippocampus. Electrical footshock stress (FSS) was administered at 8 weeks old, the time at which neurons being recruited to granule cell layer were those that had begun their differentiation at 4 weeks of age, during X-irradiation. X-irradiated mice subjected to FSS during adolescence exhibited decreased locomotor activity in the novel open field, and showed prepulse inhibition deficits in adulthood. X-irradiation or FSS alone exerted no effects on these behaviors.
These results suggest that mice with decreased postnatal neurogenesis during adolescence exhibit vulnerability to stress, and that persistence of this condition may result in decreased activity, and cognitive deficits in adulthood.
PMCID: PMC2628657  PMID: 19091092
8.  Activin in the Brain Modulates Anxiety-Related Behavior and Adult Neurogenesis 
PLoS ONE  2008;3(4):e1869.
Activin, a member of the transforming growth factor-β superfamily, is an endocrine hormone that regulates differentiation and proliferation of a wide variety of cells. In the brain, activin protects neurons from ischemic damage. In this study, we demonstrate that activin modulates anxiety-related behavior by analyzing ACM4 and FSM transgenic mice in which activin and follistatin (which antagonizes the activin signal), respectively, were overexpressed in a forebrain-specific manner under the control of the αCaMKII promoter. Behavioral analyses revealed that FSM mice exhibited enhanced anxiety compared to wild-type littermates, while ACM4 mice showed reduced anxiety. Importantly, survival of newly formed neurons in the subgranular zone of adult hippocampus was significantly decreased in FSM mice, which was partially rescued in ACM4/FSM double transgenic mice. Our findings demonstrate that the level of activin in the adult brain bi-directionally influences anxiety-related behavior. These results further suggest that decreases in postnatal neurogenesis caused by activin inhibition affect an anxiety-related behavior in adulthood. Activin and its signaling pathway may represent novel therapeutic targets for anxiety disorder as well as ischemic brain injury.
PMCID: PMC2270335  PMID: 18382659
9.  Analysis of the role of Aurora B on the chromosomal targeting of condensin I 
Nucleic Acids Research  2007;35(7):2403-2412.
During mitosis, chromosome condensation takes place, which entails the conversion of interphase chromatin into compacted mitotic chromosomes. Condensin I is a five-subunit protein complex that plays a central role in this process. Condensin I is targeted to chromosomes in a mitosis-specific manner, which is regulated by phosphorylation by mitotic kinases. Phosphorylation of histone H3 at serine 10 (Ser10) occurs during mitosis and its physiological role is a longstanding question. We examined the function of Aurora B, a kinase that phosphorylates Ser10, in the chromosomal binding of condensin I and mitotic chromosome condensation, using an in vitro system derived from Xenopus egg extract. Aurora B depletion from a mitotic egg extract resulted in the loss of H3 phosphorylation, accompanied with a 50% reduction of chromosomal targeting of condensin I. Alternatively, a portion of condensin I was bound to sperm chromatin, and chromosome-like structures were assembled when okadaic acid (OA) was supplemented in an interphase extract that lacks Cdc2 activity. However, chromosomal targeting of condensin I was abolished when Aurora B was depleted from the OA-treated interphase extract. From these results, it is suggested that Aurora B-dependent and Cdc2-independent pathways of the chromosomal targeting of condensin I are present.
PMCID: PMC1874644  PMID: 17392339
10.  Turning Off Estrogen Receptor β-Mediated Transcription Requires Estrogen-Dependent Receptor Proteolysis▿  
Molecular and Cellular Biology  2006;26(21):7966-7976.
Recent studies have shed light on the ligand-dependent transactivation mechanisms of nuclear receptors (NRs). When the ligand dose is reduced, the transcriptional activity of NRs should be downregulated. Here we show that a ubiquitin-proteasome pathway plays a key role in turning off transcription mediated by estrogen receptor β (ERβ). ERβ shows estrogen-dependent proteolysis, and its degradation is regulated by two regions in the receptor. The N-terminal 37-amino acid-region is necessary for the recruitment of the ubiquitin ligase, i.e., the carboxyl terminus of HSC70-interacting protein (CHIP), to degrade ERβ. In contrast, the C-terminal F domain protects ligand-unbound ERβ from proteolysis to abrogate proteasome association. Suppression of CHIP by interfering RNA inhibited this switching off of receptor-mediated transcription when the ligand dose was reduced. Our results suggest that after ligand withdrawal, the active form of the NR is selectively eliminated via ligand-dependent proteolysis to downregulate receptor-mediated transcription.
PMCID: PMC1636734  PMID: 16940184
11.  Transcriptional regulation of the mouse steroid 5α-reductase type II gene by progesterone in brain 
Nucleic Acids Research  2002;30(6):1387-1393.
The steroid 5α-reductase (5α-R) plays an important physiological role in the conversion of steroid hormones such as androgen and progesterone to their 5α-reduced derivatives. 5α-R type II (5α-R2), one of two 5α-R isoforms, is thought to be a key enzyme in the generation of neuroactive steroids in the brain, particularly allopregnanolone (AP), via the production of its precursor dihydroprogesterone from progesterone. In the present study, we investigated possible regulatory mechanisms of 5α-R2 gene expression by steroid hormones in the female mouse brain. We first cloned mouse 5α-R2 (m5α-R2) cDNA by degenerate PCR, and found that progesterone induced 5α-R2 gene expression to levels detectable by in situ hybridization in female mouse brains. Functional analysis of the m5α-R2 gene promoter by a transient expression assay with human progesterone receptor (PR) and androgen receptor (AR) expression vectors identified a progesterone and androgen regulatory element (m5α-R2 PRE/ARE). Results of an electrophoretic mobility shift assay revealed that both PR and AR homodimers bound directly to m5α-R2 PRE/ARE sequence. These findings suggest that the gene expression of m5α-R2 is transcriptionally regulated by progesterone in female brains.
PMCID: PMC101357  PMID: 11884637
12.  Selective Interaction of Vitamin D Receptor with Transcriptional Coactivators by a Vitamin D Analog 
Molecular and Cellular Biology  1999;19(2):1049-1055.
The nuclear vitamin D receptor (VDR) is a member of a nuclear receptor superfamily and acts as a ligand-dependent transcription factor. A family of cotranscriptional activators (SRC-1, TIF2, and AIB-1) interacts with and activates the transactivation function of nuclear receptors in a ligand-dependent way. We examined interaction of VDR with these coactivators that was induced by several vitamin D analogs, since they exert differential subsets of the biological action of vitamin D through unknown mechanisms. Unlike other vitamin D analogs tested, OCT (22-oxa-1α,25-dihydroxyvitamin D3) induced interaction of VDR with TIF2 but not with SRC-1 or AIB-1. Consistent with these interactions, only TIF2 was able to potentiate the transactivation function of VDR bound to OCT. Thus, the present findings suggest that the structure of VDR is altered in a vitamin D analog-specific way, resulting in selective interactions of VDR with coactivators. Such selective interaction of coactivators with VDR may specify the array of biological actions of a vitamin D analog like OCT, possibly through activating a particular set of target gene promoters.
PMCID: PMC116035  PMID: 9891040

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