Biomedical subjects

Rika Nakayama

Publications and source records attributed to Rika Nakayama.

8 recordsLinked to original sources

PubMed2007

[Present status of the use of adjuvant analgesics in Japan].

Adjuvant analgesics are drugs that have primary indications other than pain but are analgesic in selected circumstances. Antidepressants, anticonvulsants, local anesthetics, and NMDA receptor antagonists are drugs used in the treatment of neuropathic cancer pain. Assessment of pain is very important in selecting appropriate adjuvant analgesics. The assessment includes visual analog scale for pain intensity, McGill Pain Questionaire for quality of pain, and the location of pain. It is also important to assess the effectiveness of immediate release opioids. Most neuropathic pain is thought to be refractory to opioids. In Japan, effective adjuvant analgesics such as gabapentin and pregabalin are not available. The main adjuvant analgesics are still tricyclic antidepressants such as amytriptylin and amoxapin, and anticonvulsants such as carbamazepin and clonazepam. Another problem is that morphine is the only rescue drug available for the assessment of opioid responsiveness since morphine is the only opioid with an immediately release form among the strong opioids available in Japan which are morphine, oxycodone, and fentanyl. Adjuvant analgesics also have side effects such as constipation and sleepiness, which may augment the side effects of morphine and may impair the QOL of cancer patients with neuropathic pain. There is a need to improve the systems of development and importation of adjuvant analgesics.

Anticonvulsants↗

PubMed2006

Evolutionary constraint on Otx2 neuroectoderm enhancers-deep conservation from skate to mouse and unique divergence in teleost.

Otx2 is a paired type homeobox gene that plays essential roles in each step and site of head development in vertebrates. In the mouse, Otx2 expression in the anterior neuroectoderm is regulated primarily by two distinct enhancers: anterior neuroectoderm (AN) and forebrain/midbrain (FM) enhancers at 92 kb and 75 kb 5'of the Otx2 locus, respectively. The AN enhancer has activity in the entire anterior neuroectoderm at headfold and early somite stages, whereas the FM enhancer is subsequently active in the future caudal forebrain and midbrain ectoderm. In tetrapods, both AN and FM enhancers are conserved, whereas the AN region is missing in teleosts, despite overt Otx2 expression in the anterior neuroectoderm. Here, we show that zebrafish and fugu FM regions drive expression not only in the forebrain and midbrain but also in the anterior neuroectoderm at headfold stage. The analysis of coelacanth and skate genomic Otx2 orthologues suggests that the utilization of the two enhancers, AN and FM, is an ancestral condition. In contrast, the AN enhancer has been specifically lost in the teleost lineage with a compensatory establishment of AN activity within the FM enhancer. Furthermore, the AN activity in the fish FM enhancer was established by recruiting upstream factors different from those that direct the tetrapod AN enhancer, yet zebrafish FM enhancer is active in both mouse and zebrafish anterior neuroectoderm at the headfold stage.

Animals↗

PubMed2006

Zinc-finger genes Fez and Fez-like function in the establishment of diencephalon subdivisions.

Fez and Fez-like (Fezl) are zinc-finger genes that encode transcriptional repressors expressed in overlapping domains of the forebrain. By generating Fez;Fezl-deficient mice we found that a redundant function of Fez and Fezl is required for the formation of diencephalon subdivisions. The caudal forebrain can be divided into three transverse subdivisions: prethalamus (also called ventral thalamus), thalamus (dorsal thalamus) and pretectum. Fez;Fezl-deficient mice showed a complete loss of prethalamus and a strong reduction of the thalamus at late gestation periods. Genetic marker analyses revealed that during early diencephalon patterning in Fez;Fezl-deficient mice, the rostral diencephalon (prospective prethalamus) did not form and the caudal diencephalon (prospective thalamus and pretectum) expanded rostrally. Fez;Fezl-deficient mice also displayed defects in the formation of the zona limitans intrathalamica (ZLI), which is located on the boundary between the prethalamus and thalamus. Fez and Fezl are expressed in the region rostral to the rostral limit of Irx1 expression, which marks the prospective position of the ZLI. Transgene-mediated misexpression of Fezl or Fez caudal to the ZLI repressed the caudal diencephalon fate and affected the formation of the Shh-expressing ZLI. These data indicate that Fez and Fezl repress the caudal diencephalon fate in the rostral diencephalon, and ZLI formation probably depends on Fez/Fezl-mediated formation of diencephalon subdivisions.

Animals↗

PubMed2005

Tead proteins activate the Foxa2 enhancer in the node in cooperation with a second factor.

The cell population and the activity of the organizer change during the course of development. We addressed the mechanism of mouse node development via an analysis of the node/notochord enhancer (NE) of Foxa2. We first identified the core element (CE) of the enhancer, which in multimeric form drives gene expression in the node. The CE was activated in Wnt/beta-catenin-treated P19 cells with a time lag, and this activation was dependent on two separate sequence motifs within the CE. These same motifs were also required for enhancer activity in transgenic embryos. We identified the Tead family of transcription factors as binding proteins for the 3' motif. Teads and their co-factor YAP65 activated the CE in P19 cells, and binding of Tead to CE was essential for enhancer activity. Inhibition of Tead activity by repressor-modified Tead compromised NE enhancer activation and notochord development in transgenic mouse embryos. Furthermore, manipulation of Tead activity in zebrafish embryos led to altered expression of foxa2 in the embryonic shield. These results suggest that Tead activates the Foxa2 enhancer core element in the mouse node in cooperation with a second factor that binds to the 5' element, and that a similar mechanism also operates in the zebrafish shield.

Animals↗

PubMed2005

Ssdp1 regulates head morphogenesis of mouse embryos by activating the Lim1-Ldb1 complex.

The transcriptional activity of LIM-homeodomain (LIM-HD) proteins is regulated by their interactions with various factors that bind to the LIM domain. We show that reduced expression of single-stranded DNA-binding protein 1 (Ssdp1), which encodes a co-factor of LIM domain interacting protein 1 (Ldb1), in the mouse mutant headshrinker (hsk) disrupts anterior head development by partially mimicking Lim1 mutants. Although the anterior visceral endoderm and the anterior definitive endoderm, which together comprise the head organizer, were able to form normally in Ssdp1(hsk/hsk) mutants, development of the prechordal plate was compromised. Head development is partially initiated in Ssdp1(hsk/hsk) mutants, but neuroectoderm tissue anterior to the midbrain-hindbrain boundary is lost, without a concomitant increase in apoptosis. Cell proliferation is globally reduced in Ssdp1(hsk/hsk) mutants, and approximately half also exhibit smaller body size, similar to the phenotype observed in Lim1 and Ldb1 mutants. We also show that Ssdp1 contains an activation domain and is able to enhance transcriptional activation through a Lim1-Ldb1 complex in transfected cells, and that Ssdp1 interacts genetically with Lim1 and Ldb1 in both head development and body growth. These results suggest that Ssdp1 regulates the development of late head organizer tissues and body growth by functioning as an essential activator component of a Lim1 complex through interaction with Ldb1.

Animals↗

PubMed2005

Expression of the mouse Fgf15 gene is directly initiated by Sonic hedgehog signaling in the diencephalon and midbrain.

Sonic hedgehog (Shh) is a secreted molecule that is thought to regulate tissue growth and patterning in vertebrate embryos. Although it has been reported that Gli transcription factors mediate Shh signaling to the nucleus, little is known about developmental target genes of Gli. In the previous genetic study, we showed that Shh is required for Fgf15 expression in the diencephalon and midbrain. Here, we examined whether Fgf15 is a direct target of Shh signaling through Gli. Shh was expressed in the midline cells and Fgf15 in the medial region of the diencephalon/midbrain by the seven-somite stage. The Fgf15 expression domain coincided with that of Gli1 and overlapped with that of Gli2 at this stage. Fgf15 expression in the diencephalon/midbrain was greatly reduced in the seven-somite Shh mutant embryos. Transgenic analysis showed that the 3.6-kb 5'-flanking region of the Fgf15 gene is sufficient for induction of Fgf15 in the medial/ventral diencephalon/midbrain. Luciferase assay showed that the 3.6-kb Fgf15 enhancer/promoter was activated by Gli2. A Gli-binding site was located 1 kb upstream of the transcription start site and was required for expression in the medial/ventral diencephalon/midbrain in transgenic embryos and for activation in luciferase assay. These findings indicate that Fgf15 is directly regulated by Shh signaling through Gli proteins.

Amino Acid Motifs↗

PubMed2004

Regulation of Otx2 expression and its functions in mouse epiblast and anterior neuroectoderm.

We have identified cis-regulatory sequences acting on Otx2 expression in epiblast (EP) and anterior neuroectoderm (AN) at about 90 kb 5' upstream. The activity of the EP enhancer is found in the inner cell mass at E3.5 and the entire epiblast at E5.5. The AN enhancer activity is detected initially at E7.0 and ceases by E8.5; it is found later in the dorsomedial aspect of the telencephalon at E10.5. The EP enhancer includes multiple required domains over 2.3 kb, and the AN enhancer is an essential component of the EP enhancer. Mutants lacking the AN enhancer have demonstrated that these cis-sequences indeed regulate Otx2 expression in EP and AN. At the same time, our analysis indicates that another EP and AN enhancer must exist outside of the -170 kb to +120 kb range. In Otx2DeltaAN/- mutants, in which one Otx2 allele lacks the AN enhancer and the other allele is null, anteroposterior axis forms normally and anterior neuroectoderm is normally induced. Subsequently, however, forebrain and midbrain are lost, indicating that Otx2 expression under the AN enhancer functions to maintain anterior neuroectoderm once induced. Furthermore, Otx2 under the AN enhancer cooperates with Emx2 in diencephalon development. The AN enhancer region is conserved among mouse, human and Xenopus; moreover, the counterpart region in Xenopus exhibited an enhancer activity in mouse anterior neuroectoderm.

Alleles↗

PubMed2004

Regulation of Otx2 expression and its functions in mouse forebrain and midbrain.

Otx2 expression in the forebrain and midbrain was found to be regulated by two distinct enhancers (FM and FM2) located at 75 kb 5' upstream and 115 kb 3' downstream. The activities of these two enhancers were absent in anterior neuroectoderm earlier than E8.0; however, at E9.5 their regions of activity spanned the entire mesencephalon and diencephalon with their caudal limits at the boundary with the metencephalon or isthmus. In telencephalon, activities were found only in the dorsomedial aspect. Potential binding sites of OTX and TCF were essential to FM activity, and TCF sites were also essential to FM2 activity. The FM2 enhancer appears to be unique to rodent; however, the FM enhancer region is deeply conserved in gnathostomes. Studies of mutants lacking FM or FM2 enhancer demonstrated that these enhancers indeed regulate Otx2 expression in forebrain and midbrain. Development of mesencephalic and diencephalic regions was differentially regulated in a dose-dependent manner by the cooperation between Otx1 and Otx2 under FM and FM2 enhancers: the more caudal the structure the higher the OTX dose requirement. At E10.5 Otx1-/-Otx2DeltaFM/DeltaFM mutants, in which Otx2 expression under the FM2 enhancer remained, exhibited almost complete loss of the entire diencephalon and mesencephalon; the telencephalon did, however, develop.

Alleles↗