Language：English   Publishing type：Research paper (scientific journal)  

The endocardium is the endothelial component of the vertebrate heart and plays a key role in heart development. Where, when, and how the endocardium segregates during embryogenesis have remained largely unknown, however. We now show that Nkx2-5⁺ cardiac progenitor cells (CPCs) that express the Sry-type HMG box gene Sox17 from embryonic day (E) 7.5 to E8.5 specifically differentiate into the endocardium in mouse embryos. Although Sox17 is not essential or sufficient for endocardium fate, it can bias the fate of CPCs toward the endocardium. On the other hand, Sox17 expression in the endocardium is required for heart development. Deletion of Sox17 specifically in the mesoderm markedly impaired endocardium development with regard to cell proliferation and behavior. The proliferation of cardiomyocytes, ventricular trabeculation, and myocardium thickening were also impaired in a non-cell-autonomous manner in the Sox17 mutant, likely as a consequence of down-regulation of NOTCH signaling. An unknown signal, regulated by Sox17 and required for nurturing of the myocardium, is responsible for the reduction in NOTCH-related genes in the mutant embryos. Our results thus provide insight into differentiation of the endocardium and its role in heart development.

DOI： 10.1038/s41598-019-48321-y

Language：English   Publishing type：Research paper (scientific journal)  

GPCRs are involved in numerous physiologic functions and are important drug targets. Although the epithelial barrier is important for protection from invading pathogens, the correlation between GPCRs and epithelial barrier function remains unknown. Leukot

DOI： 10.1096/fj

Language：English   Publishing type：Research paper (scientific journal)  

Congenital heart defects with heterotaxia are associated with pregestational diabetes mellitus. To provide insight into the mechanisms underlying such diabetes-related heart defects, we examined the effects of high-glucose concentrations on formation of t

DOI： 10.1073/pnas.

Language：English   Publishing type：Research paper (scientific journal)  

Epiblast stem cells (EpiSCs) are primed pluripotent stem cells and can be derived from postimplantation mouse embryos. We now show that the absence of canonical Wnt/β-catenin signaling is essential for maintenance of the undifferentiated state in mouse EpiSCs and in the epiblast of mouse embryos. Attenuation of Wnt signaling with the small-molecule inhibitor XAV939 or deletion of the β-catenin gene blocked spontaneous differentiation of EpiSCs toward mesoderm and enhanced the expression of pluripotency factor genes, allowing propagation of EpiSCs as a homogeneous population. EpiSCs were efficiently established and propagated from single epiblast cells in the presence of both XAV939 and the Rho kinase (ROCK) inhibitor Y27632. Cell transplantation revealed that EpiSCs were able to contribute to primordial germ cells and descendants of all three germ layers in a host embryo, suggesting that they maintained pluripotency, even after prolonged culture with XAV939. Such an improvement in the homogeneity of pluripotency achieved with the use of a Wnt inhibitor should prove advantageous for manipulation of primed pluripotent stem cells.

DOI： 10.1371/journal.pone.0063378

Language：English   Publishing type：Research paper (scientific journal)  

The mouse inner ear develops from a simple epithelial pouch, the otocyst, with the dorsal and ventral portions giving rise to the vestibule and cochlea, respectively. The otocyst undergoes a morphological change to generate flattened saclike structures, known as outpocketings, in the dorsal and lateral regions. The semicircular canals of the vestibule form from the periphery of the outpocketings, with the central region (the fusion plate) undergoing de-epithelialization and disappearing. However, little is known of the mechanism that orchestrates formation of the semicircular canals. We now show that the area of canonical Wnt signaling changes dynamically in the dorsal otocyst during its morphogenesis. The genes for several Wnt ligands were found to be expressed in the dorsal otocyst according to specific patterns, whereas those for secreted inhibitors of Wnt ligands were expressed exclusively in the ventral otocyst. With the use of whole-embryo culture in combination with potent modulators of canonical Wnt signaling, we found that forced persistence of such signaling resulted in impaired formation both of the lateral outpocketing and of the fusion plates of the dorsal outpocketing. Canonical Wnt signaling was found to suppress Netrin1 expression and to preserve the integrity of the outpocketing epithelium. In addition, inhibition of canonical Wnt signaling reduced the size of the otocyst, likely through suppression of cell proliferation and promotion of apoptosis. Our stage-specific functional analysis suggests that strict regulation of canonical Wnt signaling in the dorsal otocyst orchestrates the process of semicircular canal formation.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1161/CIRCRESAHA.110.223388

Event date： 2018.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：パシフィコ横浜   Country：Japan  

Event date： 2018.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：パシフィコ横浜   Country：Japan  

Event date： 2017.8

Language：Japanese  

Country：Japan  

Event date： 2014.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：パシフィコ横浜   Country：Japan  

先天性心疾患はヒトで最も頻発する先天異常の一つであり、最近の研究によると新生児の罹患率は約１％である。先天性心疾患は必ずしも遺伝学的な異常によって起こるものではなく、様々な環境要因が特定の先天性心疾患の発生リスクを高めることが疫学調査から明らかになっている。妊娠前糖尿病はそのような環境要因の一つである。妊娠前糖尿病に関連した先天性心疾患に特徴的なのは、これに内臓錯位を伴うケースが存在することである。しかしながら、高血糖症によって先天性心疾患が引き起こされる仕組みは、臨床的にも重要な問題であるにも関わらず、ほとんど明らかになっていない。　臓器の左右非対称性は発生初期に確立される左右軸に基づいて形成される。糖尿病に関連して心疾患及び内臓錯位が発生する分子機構を解明するため、ストレプトゾシンによる糖尿病雌マウスに由来する胚、及び高濃度グルコース培地で培養したマウス胚における左右軸形成を解析した。その結果、高濃度グルコースは心臓形態形成に必要な左右軸の確立を撹乱することが明らかになった。この年会では、最新のデータを提示すると共に、妊娠前糖尿病に関連した先天性心疾患の発生機序について話したい。

Event date： 2013.8

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：ホテルセキア   Country：Japan  

The node triggers formation of the left-right axis in mouse embryos by establishing local asymmetry of Nodal and Cerl2 expression. We found that Wnt3 is expressed in perinodal crown cells preferentially on the left side. The enhancer responsible for Wnt3 expression was identified and found to be regulated by Foxa2 and Rbpj under the control of Notch signaling. Rbpj binding sites suppress enhancer activity in pit cells of the node, thereby ensuring crown cell–specific expression. In addition, we found that the expression of Gdf1 and Cerl2 is also regulated by Notch signaling, suggesting that such signaling may induce the expression of genes related to left-right asymmetry as a set. Furthermore, Cerl2 expression became symmetric in response to inhibition of Wnt–β-catenin signaling. Our results suggest that Wnt signaling regulates the asymmetry of Cerl2 expression, which likely generates a left-right difference in Nodal activity at the node for further amplification in lateral plate mesoderm.

Audience：Infants,　Schoolchildren,　Junior students,　High school students

Type：Seminar, workshop

Audience：Infants,　Schoolchildren,　Junior students,　High school students

Type：Seminar, workshop

Audience：Infants,　Schoolchildren,　Junior students,　High school students

Type：Seminar, workshop

Audience：Infants,　Schoolchildren,　Junior students,　High school students

Type：Seminar, workshop

Type：Science cafe

researchmap