Wnt/Dkk Negative Feedback Regulates Sensory Organ Size in Zebrafish

SummaryCorrect organ size must involve a balance between promotion and inhibition of cell proliferation. A mathematical model has been proposed in which an organ is assumed to produce its own growth activator as well as a growth inhibitor [1], but there is as yet no molecular evidence to support this model [2]. The mechanosensory organs of the fish lateral line system (neuromasts) are composed of a core of sensory hair cells surrounded by nonsensory support cells. Sensory cells are constantly replaced and are regenerated from surrounding nonsensory cells [3], while each organ retains the same size throughout life. Moreover, neuromasts also bud off new neuromasts, which stop growing when they reach the same size [4, 5]. Here, we show that the size of neuromasts is controlled by a balance between growth-promoting Wnt signaling activity in proliferation-competent cells and Wnt-inhibiting Dkk activity produced by differentiated sensory cells. This negative feedback loop from Dkk (secreted by differentiated cells) on Wnt-dependent cell proliferation (in surrounding cells) also acts during regeneration to achieve size constancy. This study establishes Wnt/Dkk as a novel mechanism to determine the final size of an organ

Left atrial metastasis of renal cell carcinoma: a case report and review of the literature

Background: Cardiac metastasis of renal cell carcinoma is an exceptional event, particularly when there is lack of inferior vena cava involvement. Indeed, only a few cases have been reported worldwide thus far. Moreover, discussion of treatment and follow-up strategies for cardiac metastasis of renal cell carcinoma is important because of the high risk of sudden death. Case presentation. We report the case of a 75-year-old Japanese man with metastatic tumor in the left atrium from renal cell carcinoma. He had a history of right renal cell carcinoma, for which he had undergone hand-assisted laparoscopic nephrectomy. Lung and bone metastases were detected after nephrectomy, and treatment with interferon-alpha was initiated. After disease progression, he was treated concurrently with targeted molecular therapy and radiotherapy for bone metastasis. After these therapies, a 42 × 24 mm mass was found on transthoracic echocardiography in left atrium without involvement of the right atrium or inferior vena cava. The provisional diagnosis was metastatic mass or myxoma, and surgical resection was performed. Histopathological examination led to a final diagnosis of metastatic tumor from clear cell renal cell carcinoma. Conclusion: Cardiac metastasis, metastasis to the left atrium in particular, is rare in patients with renal cell carcinoma. In our study, surgery of the cardiac mass was effective to avoid sudden death and quality of life decline resulting from heart failure. We describe this case and review cardiac metastasis of renal cell carcinoma

Aseptic Meningoencephalitis Complicated by Retrobulbar Neuritis

A 25-year-old man was admitted to our hospital for testing and follow-up of aseptic meningoencephalitis. After admission to our hospital, the patient suddenly complained of visual field disorder and a decrease of visual acuity in the right eye. We diagnosed aseptic meningitis complicated by retrobulbar neuritis using MRI. We immediately initiated weekly steroid pulse therapy, and eventually, marked improvement in visual acuity and the visual field disorder was observed without any late effects

zTrap: zebrafish gene trap and enhancer trap database

<p>Abstract</p> <p>Background</p> <p>We have developed genetic methods in zebrafish by using the <it>Tol2 </it>transposable element; namely, transgenesis, gene trapping, enhancer trapping and the Gal4FF-UAS system. Gene trap constructs contain a splice acceptor and the GFP or Gal4FF (a modified version of the yeast Gal4 transcription activator) gene, and enhancer trap constructs contain the zebrafish <it>hsp70l </it>promoter and the GFP or Gal4FF gene. By performing genetic screens using these constructs, we have generated transgenic zebrafish that express GFP and Gal4FF in specific cells, tissues and organs. Gal4FF expression is visualized by creating double transgenic fish carrying a Gal4FF transgene and the GFP reporter gene placed downstream of the Gal4-recognition sequence (UAS). Further, the Gal4FF-expressing cells can be manipulated by mating with UAS effector fish. For instance, when fish expressing Gal4FF in specific neurons are crossed with the UAS:TeTxLC fish carrying the tetanus neurotoxin gene downstream of UAS, the neuronal activities are inhibited in the double transgenic fish. Thus, these transgenic fish are useful to study developmental biology and neurobiology.</p> <p>Description</p> <p>To increase the usefulness of the transgenic fish resource, we developed a web-based database named <it>z</it>Trap <url>http://kawakami.lab.nig.ac.jp/ztrap/</url>. The <it>z</it>Trap database contains images of GFP and Gal4FF expression patterns, and genomic DNA sequences surrounding the integration sites of the gene trap and enhancer trap constructs. The integration sites are mapped onto the <it>Ensembl </it>zebrafish genome by in-house Blat analysis and can be viewed on the <it>z</it>Trap and <it>Ensembl </it>genome browsers. Furthermore, <it>z</it>Trap is equipped with the functionality to search these data for expression patterns and genomic loci of interest. <it>z</it>Trap contains the information about transgenic fish including UAS reporter and effector fish.</p> <p>Conclusion</p> <p><it>z</it>Trap is a useful resource to find gene trap and enhancer trap fish lines that express GFP and Gal4FF in desired patterns, and to find insertions of the gene trap and enhancer trap constructs that are located within or near genes of interest. These transgenic fish can be utilized to observe specific cell types during embryogenesis, to manipulate their functions, and to discover novel genes and <it>cis</it>-regulatory elements. Therefore, <it>z</it>Trap should facilitate studies on genomics, developmental biology and neurobiology utilizing the transgenic zebrafish resource.</p

Clinical and genetic characteristics of autoimmune polyglandular syndrome type 3 variant in the Japanese population

Objective: Type 1 diabetes (T1D) iscommonlyassociated withautoimmunethyroid disease (AITD),and the occurrence of both T1D and AITD in a patient is defined as autoimmune polyglandular syndrome type 3 variant (APS3v). We aimed to clarify the differences in the clinical and genetic characteristics of APS3v patients and T1D patients without AITD [T1D/AITD(-)] in the Japanese population. Design/Patients: Our subjects were 54 APS3v patients and 143 T1D/AITD(-) patients who were consecutively diagnosed at Nagasaki University Hospital from 1983 to the present. Results: A remarkable female predominance, a slow and older age onset of T1D, and a higher prevalence of glutamic acid decarboxylase autoantibodies were observed in APS3v patients compared to T1D/AITD(-) patients. The older onset age of T1D in APS3v patients was associated with a higher proportion of slow-onset T1D. Among the two major susceptible human leukocyte antigen (HLA) class II haplotypes in Japanese T1D, DRB1*0405- DQB1*0401, but not DRB1*0901-DQB1*0303, was associated with APS3v patients. Furthermore, DRB1*0803-DQB1*0601 was not protective in patients with APS3v. The frequencies of the GG genotype in +49G>A and +6230G>A polymorphism in the CTLA4 gene were significantly higher in T1D/AITD(-) patients, but not in APS3v patients, compared to control subjects. Conclusions: In conclusion, we found notable differences in the clinical and genetic characteristics of APS3v patients and T1D/AITD(-) patients in the Japanese population, and the differences in the clinical characteristics between the two groups may reflect distinct genetic backgrounds including the HLA DRB1-DQB1 haplotypes and CTLA4 gene polymorphisms

Two cases of multiple infarctions due to vertebral arterial occlusion associated with atlantoaxial subluxation caused by rheumatoid arthritis

Case 1: A 58-year-old woman with rheumatoid arthritis (RA) suffered from pontine and cerebellar infarctions and underwent three-dimensional computed tomography angiography (3D-CTA) of the vertebral artery (VA) with left-sided rotation of the head. This revealed a destroyed right atlantoaxial (AA) joint and right VA occlusion, which had caused the infarction. No recurrent infarctions have been observed after transarticular screw fixation (Magerl technique) was performed. Case 2: A 68-yearold woman with RA also suffered from pontine and cerebellar infarctions and underwent 3D-CTA of the VA with right-sided rotation of the head. This revealed a destroyed left AA joint and left VA occlusion, which had caused the infarction. No recurrentinfarctions have been observed after posterior fusion between the occiput and 3rd cervical vertebra was performed. In both cases of RA, who had multiple infarctions due to VA occlusion and a temporary thrombus formation, 3D-CTA in a rotated position helped to diagnose arterial occlusion. In addition, posterior fusion of the AA joint was a useful surgical technique

Association of the GCKR rs780094 polymorphism with metabolic traits including carotid intima-media thickness in Japanese community-dwelling men, but not in women

Background: The glucokinase regulator gene (GCKR) rs780094 has been shown to be strongly associated with some metabolic traits and atherosclerotic parameters, while the association between GCKR rs780094 and carotid intima-media thickness (CIMT) has not been fully investigated in the general population. The associations between the GCKR rs780094 genotype and metabolic traits including CIMT were examined in a Japanese community-dwelling population. Methods: A total of 2491 Japanese adults (907 men and 1584 women) who participated in a medical screening program for the general population from 29 to 94 years of age during 2008 to 2010 were enrolled. GCKR rs780094 was genotyped by the TaqMan polymerase chain reaction method, and associations with metabolic markers including CIMT were evaluated. Results: GCKR rs780094 AA genotype was significantly associated with higher TG (p < 0.001 vs. GG), lower HDL-C (p = 0.021 vs. GG), and lower HbA1c (p = 0.023 vs. GG). The AA genotype showed significantly thinner CIMT (p = 0.001 vs. GX). These associations were seen only in men. Conclusions: GCKR rs780094 was associated with TG, HDL-C, and HbA1c levels, as well as with CIMT in Japanese community-dwelling men, but not women

The development and growth of tissues derived from cranial neural crest and primitive mesoderm is dependent on the ligation status of retinoic acid receptor γ:evidence that retinoic acid receptor γ functions to maintain stem/progenitor cells in the absence of retinoic acid

Retinoic acid (RA) signaling is important to normal development. However, the function of the different RA receptors (RARs)-RARα, RARβ, and RARγ-is as yet unclear. We have used wild-type and transgenic zebrafish to examine the role of RARγ. Treatment of zebrafish embryos with an RARγ-specific agonist reduced somite formation and axial length, which was associated with a loss of hoxb13a expression and less-clear alterations in hoxc11a or myoD expression. Treatment with the RARγ agonist also disrupted formation of tissues arising from cranial neural crest, including cranial bones and anterior neural ganglia. There was a loss of Sox 9-immunopositive neural crest stem/progenitor cells in the same anterior regions. Pectoral fin outgrowth was blocked by RARγ agonist treatment. However, there was no loss of Tbx-5-immunopositive lateral plate mesodermal stem/progenitor cells and the block was reversed by agonist washout or by cotreatment with an RARγ antagonist. Regeneration of the caudal fin was also blocked by RARγ agonist treatment, which was associated with a loss of canonical Wnt signaling. This regenerative response was restored by agonist washout or cotreatment with the RARγ antagonist. These findings suggest that RARγ plays an essential role in maintaining stem/progenitor cells during embryonic development and tissue regeneration when the receptor is in its nonligated state