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Yuji Mishina

Publications and source records attributed to Yuji Mishina.

50 records · Page 3Linked to original sources
PubMed2003

Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction.

Potential repair by cell grafting or mobilizing endogenous cells holds particular attraction in heart disease, where the meager capacity for cardiomyocyte proliferation likely contributes to the irreversibility of heart failure. Whether cardiac progenitors exist in adult myocardium itself is unanswered, as is the question whether undifferentiated cardiac precursor cells merely fuse with preexisting myocytes. Here we report the existence of adult heart-derived cardiac progenitor cells expressing stem cell antigen-1. Initially, the cells express neither cardiac structural genes nor Nkx2.5 but differentiate in vitro in response to 5'-azacytidine, in part depending on Bmpr1a, a receptor for bone morphogenetic proteins. Given intravenously after ischemia/reperfusion, cardiac stem cell antigen 1 cells home to injured myocardium. By using a Cre/Lox donor/recipient pair (alphaMHC-Cre/R26R), differentiation was shown to occur roughly equally, with and without fusion to host cells.

Animals↗
PubMed2003

Genetic interaction between Wnt/beta-catenin and BMP receptor signaling during formation of the AER and the dorsal-ventral axis in the limb.

By conditional gene ablation in mice, we found that beta-catenin, an essential downstream effector of canonical Wnt signaling, is a key regulator of formation of the apical ectodermal ridge (AER) and of the dorsal-ventral axis of the limbs. By generation of compound mutants, we also show that beta-catenin acts downstream of the BMP receptor IA in AER induction, but upstream or parallel in dorsal-ventral patterning. Thus, AER formation and dorsal-ventral patterning of limbs are tightly controlled by an intricate interplay between Wnt/beta-catenin and BMP receptor signaling.

Animals↗
PubMed2003

Function of bone morphogenetic protein signaling during mouse development.

Bone morphogenetic proteins (BMPs) play pleiotropic roles during development and after birth in many different organisms. BMPs are members of TGF-beta superfamily. There are more than 20 members with three type II receptors and three type I receptors. Genetic approaches using the mouse as a model system revealed many of the functions of BMPs. Particularly, results obtained through loss-of-function analyses of BMP ligands and their receptors are reviewed in this article.

Animals↗
PubMed2003

Heterozygosity with respect to Zfp148 causes complete loss of fetal germ cells during mouse embryogenesis.

Zfp148 belongs to a large family of C2H2-type zinc-finger transcription factors. Zfp148 is expressed in fetal germ cells in 13.5-d-old (E13.5) mouse embryos. Germ-line transmission of mutations were not observed in chimeric Zfp148(+/-) mice, and some of these mice completely lacked spermatogonia. The number of primordial germ cells in Zfp148(+/-) tetraploid embryos was normal until E11.5, but declined from E11.5 to E13.5 and continued to decline until few germ cells were present at E18.5. This phenotype was not rescued by wild-type Sertoli or stromal cells, and is therefore a cell-autonomous phenotype. These results indicate that two functional alleles of Zfp148 are required for the normal development of fetal germ cells. Recent studies have shown that Zfp148 activates p53, which has an important role in cell-cycle regulation. Primordial germ cells stop proliferating at approximately E13.5, which correlates with induction of phosphorylation of p53 and its translocation to the nucleus. Phosphorylation of p53 is impaired in Zfp148(+/-) embryonic stem cells and in fetal germ cells from chimeric Zfp148(+/-) embryos. Thus, Zfp148 may be required for regulating p53 in the development of germ cells.

Aging↗
PubMed2003

Whole-embryo culture of E5.5 mouse embryos: development to the gastrulation stage.

This study reports establishment of an in vitro culture system for E5.5 mouse embryos that supports development to the gastrulation stage and allows the use of experimental approaches to study gastrulation during mouse embryogenesis. Recent experiments suggest that the extraembryonic tissues may play a critical role for gastrulation from as early as E5.5. To apply whole embryo culture to E5.5 embryos and analyze gastrulation, it is essential to optimize the conditions so that most of the embryos develop to the gastrulation stage in culture. For this purpose, we established a protocol in which embryos were isolated using micromanipulator and cultured with 50-75% rat serum. Although cultured embryos tended to grow a larger extraembryonic portion, more than 80% of them developed the primitive streak and induce mesoderm, which corresponds to the mid-streak stage.

Animals↗
PubMed2002

Requirement of Bmpr1a for Müllerian duct regression during male sexual development.

Elimination of the developing female reproductive tract in male fetuses is an essential step in mammalian sexual differentiation. In males, the fetal testis produces the transforming growth factor beta (TGF-beta) family member anti-Müllerian hormone (Amh, also known as Müllerian-inhibiting substance (Mis)), which causes regression of the Müllerian ducts, the primordia of the oviducts, uterus and upper vagina. Amh induces regression by binding to a specific type II receptor (Amhr2) expressed in the mesenchyme surrounding the ductal epithelium. Mutations in AMH or AMHR2 in humans and mice disrupt signaling, producing male pseudohermaphrodites that possess oviducts and uteri. The type I receptor and Smad proteins that are required in vivo for Müllerian duct regression have not yet been identified. Here we show that targeted disruption of the widely expressed type I bone morphogenetic protein (BMP) receptor Bmpr1a (also known as Alk3) in the mesenchymal cells of the Müllerian ducts leads to retention of oviducts and uteri in males. These results identify Bmpr1a as a type I receptor for Amh-induced regression of Müllerian ducts. Because Bmpr1a is evolutionarily conserved, these findings indicate that a component of the BMP signaling pathway has been co-opted during evolution for male sexual development in amniotes.

Activin Receptors, Type I↗
PubMed2002

BMP signaling is required locally to pattern the dorsal telencephalic midline.

BMPs have been proposed to pattern the medial-lateral axis of the telencephalon in a concentration-dependent manner, thus helping to subdivide the embryonic telencephalon into distinct forebrain regions. Using a CRE/loxP genetic approach, we tested this hypothesis by disrupting the Bmpr1a gene in the telencephalon. In mutants, BMP signaling was compromised throughout the dorsal telencephalon, but only the most dorsalmedial derivative, the choroid plexus, failed to be specified or differentiate. Choroid plexus precursors remained proliferative and did not adopt the fate of their lateral telencephalic neighbors. These results demonstrate that BMP signaling is required for the formation of the most dorsal telencephalic derivative, the choroid plexus, and that BMP signaling plays an essential role in locally patterning the dorsal midline. Our data fail to support a more global, concentration-dependent role in specifying telencephalic cell fates.

Animals↗
PubMed2002

Positional cloning of the gene LIMBIN responsible for bovine chondrodysplastic dwarfism.

Chondrodysplastic dwarfism in Japanese brown cattle is an autosomal recessive disorder characterized by short limbs. Previously, we mapped the locus responsible for the disease on the distal end of bovine chromosome 6. Here, we narrowed the critical region to approximately 2 cM by using linkage analysis, constructed a BAC and YAC contig covering this region, and identified a gene, LIMBIN (LBN), that possessed disease-specific mutations in the affected calves. One mutation was a single nucleotide substitution leading to an activation of a cryptic splicing donor site and the other was a one-base deletion resulting in a frameshift mutation. Strong expression of the Lbn gene was observed in limb buds of developing mouse embryos and in proliferating chondrocytes and bone-forming osteoblasts in long bones. These findings indicate that LBN is responsible for bovine chondrodysplastic dwarfism and has a critical role in a skeletal development.

Amino Acid Sequence↗
PubMed2002

Endocardial cushion and myocardial defects after cardiac myocyte-specific conditional deletion of the bone morphogenetic protein receptor ALK3.

Receptors for bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta (TGFbeta) superfamily, are persistently expressed during cardiac development, yet mice lacking type II or type IA BMP receptors die at gastrulation and cannot be used to assess potential later roles in creation of the heart. Here, we used a Cre/lox system for cardiac myocyte-specific deletion of the type IA BMP receptor, ALK3. ALK3 was specifically required at mid-gestation for normal development of the trabeculae, compact myocardium, interventricular septum, and endocardial cushion. Cardiac muscle lacking ALK3 was specifically deficient in expressing TGFbeta2, an established paracrine mediator of cushion morphogenesis. Hence, ALK3 is essential, beyond just the egg cylinder stage, for myocyte-dependent functions and signals in cardiac organogenesis.

Animals↗
PubMed2002

Genetic studies of MIS signalling in sexual development.

The Müllerian ducts are composed of an epithelium and surrounding mesenchyme that have the potential to differentiate into female reproductive organs, including the oviducts, uterus and upper vagina. In eutherian mammals, Müllerian inhibiting substance/anti-Müllerian hormone (MIS/AMH) secreted by the fetal testis causes the regression of the Müllerian ducts to prevent the differentiation of female reproductive organs in males. MIS signalling in the Müllerian duct is mediated by the MIS type II receptor (MISRII) that is expressed in the mesenchyme surrounding the epithelium. MIS signalling alters the Müllerian duct mesenchyme, leading to the elimination of the ductal epithelium. Loss of MIS signalling, by mutation of MIS or MISRII, leads to the differentiation of female reproductive organs in males that can cause cryptorchidism and infertility. We have exploited the mouse MisrII locus to express heterologous genes in the cellular target of MIS signalling, the Müllerian duct mesenchyme. This approach can be used with conditional genetic strategies to identify factors that are required for the regression of the female genital duct system.

Animals↗
PubMed2002

BMPs and BMP receptors in mouse metanephric development: in vivo and in vitro studies.

BMPs have recently emerged as likely regulators of development of the permanent kidney (metanephros). Transcripts for BMPs and their receptors have been localised in the developing metanephros. In vitro, BMPs 2, 4 and 7 have direct or indirect roles in regulation of ureteric branching morphogenesis and branch formation. In vivo, renal phenotypes have been reported in BMP7 homozygous null mutant mice and BMP4 heterozygous null mutant mice. In the present study, in vivo and in vitro roles of BMPs and BMP receptors in metanephric development were further analysed. Stereology and histology were used to analyse kidneys from mice heterozygous for mutations in either BMP2, BMPR-IA or ActR-IA. Roles of BMPs 2 and 4 in mouse metanephric development in vitro were analysed by culturing whole metanephroi in the presence of BMP2, BMP4, the BMP inhibitor noggin, and BMP4 plus noggin. Ureteric branching morphogenesis and nephrogenesis were analysed. By qualitative histology, kidneys from BMP2, BMPR-IA and ActR-IA heterozygous null mutant mice were found to be the same as those from wild type mice. The kidneys of the heterozygous mice contained the normal complement of nephrons. In vitro, high concentrations of BMP4 inhibited branching of the ureteric epithelium and changed its morphology, while nephrogenesis was inhibited by 50%. A range of concentrations of BMP2 did not alter ureteric or mesenchyme morphology, or the number of glomeruli formed. Noggin did not alter metanephric development in vitro, but did block the effect of BMP4. The experiments described in this study have shown that BMP4 has distinct roles from BMP2 in metanephric development.

Animals↗