Akihiko Shimono

Aichi Cancer Center, Ōsaka, Ōsaka, Japan

Are you Akihiko Shimono?

Claim your profile

Publications (33)272.4 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: During eye lens development, regulation of Wnt/β-catenin signaling is critical for two major processes: initially it must be silent in the lens placode for lens development to proceed, but subsequently it is required for maintenance of the lens epithelium. It is not known how these different phases of Wnt/β-catenin activity/inactivity are regulated. Secreted frizzled related protein-2 (Sfrp2), a putative Wnt-Fz antagonist, is expressed in lens placode and in lens epithelial cells and has been put forward as a candidate for regional Wnt/β-catenin pathway regulation. Here we show its closely-related isoform, Sfrp1, has a complimentary pattern of expression in the lens, being absent from the placode and epithelium but expressed in the fibers. As mice with single knockouts of Sfrp1 or Sfrp2 had no defects in lens formation, we examined lenses of Sfrp1 and Sfrp2 double knockout (DKO) mice and showed that they formed lens placode and subsequent lens structures. Consistent with this we did not observe ectopic TCF/Lef activity in lens placode of DKOs. This indicates that Sfrp1 and Sfrp2 individually, or together, do not constitute the putative negative regulator that blocks Wnt/β-catenin signaling during lens induction. In contrast, Sfrp1 and Sfrp2 appear to have a positive regulatory function because Wnt/β-catenin signaling in lens epithelial cells was reduced in Sfrp1 and Sfrp2 DKO mice. Lenses that formed in DKO mice were smaller than controls and exhibited a deficient epithelium. Thus Sfrps play a role in lens development, at least in part, by regulating aspects of Wnt/β-catenin signaling in lens epithelial cells.
    Developmental Biology 10/2013; · 3.87 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The molecular mechanisms involved in the development of obesity and related complications remain unclear. Wnt signaling plays an important role in preadipocyte differentiation and adipogenesis. The expression of a Wnt antagonist, secreted frizzled related protein 1 (SFRP1), is increased in response to initial weight gain, then levels are reduced under conditions of extreme obesity in both humans and animals. Here we report that loss of Sfrp1 exacerbates weight gain, glucose homeostasis and inflammation in mice in response to diet induced obesity (DIO). Sfrp1(-/-) mice fed a high fat diet (HFD) exhibited an increase in body mass accompanied by increases in body fat percentage, visceral white adipose tissue (WAT) mass, and adipocyte size. Moreover, Sfrp1 deficiency increases the mRNA levels of key de novo lipid synthesis genes (Fasn, Acaca, Acly, Elovl, Scd1) and the transcription factors that regulate their expression (Lxr-α, Srebp1, Chreb, and Nr1h3) in WAT. Fasting glucose levels are elevated, glucose clearance is impaired, hepatic gluconeogenesis regulators are aberrantly upregulated (G6pc and Pck1), and glucose transporters are repressed (Slc2a2 and Slc2a4) in Sfrp1(-/-) mice fed a HFD. Additionally, we observed increased steatosis in the livers of Sfrp1(-/-) mice. When there is an expansion of adipose tissue there is a sustained inflammatory response accompanied by adipokine dysregulation, which leads to chronic subclinical inflammation. Thus, we assessed the inflammatory state of different tissues and revealed that Sfrp1(-/-) mice fed a HFD exhibited increased macrophage infiltration and expression of pro-inflammatory markers including IL-6, Nmnat, Tgf-β2, and SerpinE1. Our findings demonstrate that the expression of Sfrp1 is a critical factor required for maintaining appropriate cellular signaling in response to the onset of obesity.
    PLoS ONE 01/2013; 8(12):e78320. · 3.73 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: The Hippo-Yap signaling pathway regulates a number of developmental and adult cellular processes, including cell fate determination, tissue growth, and tumorigenesis. Members of the scaffold protein angiomotin (Amot) family interact with several Hippo pathway components, including Yap (Yes-associated protein), and either stimulate or inhibit Yap activity. We used a combination of genetic, biochemical, and transcriptional approaches to assess the functional consequences of the Amot-Yap interaction in mice and in human cells. Mice with a liver-specific Amot knockout exhibited reduced hepatic "oval cell" proliferation and tumorigenesis in response to toxin-induced injury or when crossed with mice lacking the tumor suppressor Nf2. Biochemical examination of the Amot-Yap interaction revealed that the p130 splicing isoform of Amot (Amot-p130) and Yap interacted in both the cytoplasm and nucleus, which involved binding of PPxY and LPxY motifs in Amot-p130 to WW domains of Yap. In the cytoplasm, Amot-p130 prevented the phosphorylation of Yap by blocking access of the WW domains to the kinase Lats1. Within the nucleus, Amot-p130 was associated with the transcriptional complex containing Yap and Teads (TEA domain family members) and contributed to the regulation of a subset of Yap target genes, many of which are associated with tumorigenesis. These findings indicated that Amot acts as a Yap cofactor, preventing Yap phosphorylation and augmenting its activity toward a specific set of genes that facilitate tumorigenesis.
    Science Signaling 01/2013; 6(291):ra77. · 7.65 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: BACKGROUND: Secreted frizzled-related proteins (SFRPs) are a family of proteins that block the Wnt signaling pathway and loss of SFRP1 expression is found in breast cancer along with a multitude of other human cancers. Activated Wnt signaling leads to inappropriate mammary gland development and mammary tumorigenesis in mice. When SFRP1 is knocked down in immortalized non-malignant mammary epithelial cells, the cells exhibit a malignant phenotype which resembles the characteristics observed in metastatic breast cancer stem-like cells. However, the effects of SFRP1 loss on mammary gland development in vivo are yet to be elucidated. The work described here was initiated to investigate the role of SFRP1 in mammary gland development and whether SFRP1/ mice exhibit changes in mammary gland morphology and cell signaling pathways shown to be associated with SFRP1 loss in vitro. RESULTS: 10 week old nulliparous SFRP1/ mammary glands exhibited branching with clear lobulo-alveolar development, which normally only occurs in hormonally stimulated mid-pregnant wt mammary glands. Explant cultures of SFRP1/ mammary glands display increased levels of a well known Wnt signaling target gene, Axin2. Histomorphologic evaluation of virgin glands revealed that by 10 weeks of age, the duct profile is markedly altered in SFRP1/ mice showing a significantly higher density of ducts with distinct alveoli present throughout the mammary gland, and with focal ductal epithelial hyperplasia. These findings persist as the mice age and are evident at 23 weeks of age. Changes in gene expression, including c-Myc, TGFbeta-2, Wnt4, RANKL, and Rspo2 early in mammary gland development are consistent with the excessive hyper branching phenotype. Finally, we found that loss of SFRP1 significantly increases the number of mammary epithelial cells capable of mammosphere formation. CONCLUSIONS: Our study indicates that SFRP1 gene is critical for maintaining proper mammary gland development, and that reduced levels of SFRP1 results in hyperplastic lesions and its loss may be a critical event in cancer initiation.
    BMC Developmental Biology 08/2012; 12(1):25. · 2.73 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Secreted Frizzled related proteins (sFRPs) are a family of proteins that modulate Wnt signaling, which in turn regulates multiple aspects of ventral midbrain (VM) and dopamine (DA) neuron development. However, it is not known which Wnt signaling branch and what aspects of midbrain DA neuron development are regulated by sFRPs. Here, we show that sFRP1 and sFRP2 activate the Wnt/planar-cell-polarity/Rac1 pathway in DA cells. In the developing VM, sFRP1 and sFRP2 are expressed at low levels, and sFRP1-/- or sFRP2-/- mice had no detectable phenotype. However, compound sFRP1-/-;sFRP2-/- mutants revealed a Wnt/PCP phenotype similar to that previously described for Wnt5a-/- mice. This included an anteroposterior shortening of the VM, a lateral expansion of the Shh domain and DA lineage markers (Lmx1a and Th), as well as an accumulation of Nurr1+ precursors in the VM. In vitro experiments showed that, while very high concentrations of SFRP1 had a negative effect on cell survival, low/medium concentrations of sFRP1 or sFRP2 promoted the DA differentiation of progenitors derived from primary VM cultures or mouse embryonic stem cells (ESCs), mimicking the effects of Wnt5a. We thus conclude that the main function of sFRP1 and sFRP2 is to enhance Wnt/PCP signaling in DA cells and to regulate Wnt/PCP-dependent functions in midbrain development. Moreover, we suggest that low-medium concentrations of sFRPs may be used to enhance the DA differentiation of ESCs and improve their therapeutic application.
    Stem Cells 01/2012; 30(5):865-75. · 7.70 Impact Factor
  • Makoto Matsuyama, Akihiko Shimono
    [show abstract] [hide abstract]
    ABSTRACT: Recent accumulating data indicate links between planer cell polarity (PCP) and apicobasal (AB) polarity in epithelial cells. PCP regulatory genes have been shown to be involved in the establishment of AB polarity in addition to regulating PCP. We have shown that the gut tube of the mouse embryo is a unique model system for the analysis of epithelial polarities, e.g., oriented cell division and AB polarity, with respect to the PCP pathway. The regulation of epithelial polarity by the PCP pathway might play an essential role in organ morphogenesis relating to physiological function.
    Methods in molecular biology (Clifton, N.J.) 01/2012; 839:229-37.
  • [show abstract] [hide abstract]
    ABSTRACT: Secreted frizzled-related proteins (Sfrps) are considered Wnt signalling antagonists but recent studies have shown that specific family members enhance Wnt diffusion and thus positively modulate Wnt signalling. Whether this is a general and physiological property of all Sfrps remains unexplored. It is equally unclear whether disruption of Sfrp expression interferes with developmental events mediated by Wnt signalling activation. Here, we have addressed these questions by investigating the functional consequences of Sfrp disruption in the canonical Wnt signalling-dependent specification of the mouse optic cup periphery. We show that compound genetic inactivation of Sfrp1 and Sfrp2 prevents Wnt/β-catenin signalling activation in this structure, which fails to be specified and acquires neural retina characteristics. Consistent with a positive role of Sfrps in signalling activation, Wnt spreading is impaired in the retina of Sfrp1(-/-);Sfrp2(-/-) mice. Conversely, forced expression of Sfrp1 in the wing imaginal disc of Drosophila, the only species in which the endogenous Wnt distribution can be detected, flattens the Wg gradient, suppresses the expression of high-Wg target genes but expands those typically activated by low Wg concentrations. Collectively, these data demonstrate that, in vivo, the levels of Wnt signalling activation strongly depend on the tissue distribution of Sfrps, which should be viewed as multifunctional regulators of Wnt signalling.
    Development 10/2011; 138(19):4179-84. · 6.60 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: It is well established that retinal neurogenesis in mouse embryos requires the activation of Notch signaling, but is independent of the Wnt signaling pathway. We found that genetic inactivation of Sfrp1 and Sfrp2, two postulated Wnt antagonists, perturbs retinal neurogenesis. In retinas from Sfrp1(-/-); Sfrp2(-/-) embryos, Notch signaling was transiently upregulated because Sfrps bind ADAM10 metalloprotease and downregulate its activity, an important step in Notch activation. The proteolysis of other ADAM10 substrates, including APP, was consistently altered in Sfrp mutants, whereas pharmacological inhibition of ADAM10 partially rescued the Sfrp1(-/-); Sfrp2(-/-) retinal phenotype. Conversely, ectopic Sfrp1 expression in the Drosophila wing imaginal disc prevented the expression of Notch targets, and this was restored by the coexpression of Kuzbanian, the Drosophila ADAM10 homolog. Together, these data indicate that Sfrps inhibit the ADAM10 metalloprotease, which might have important implications in pathological events, including cancer and Alzheimer's disease.
    Nature Neuroscience 05/2011; 14(5):562-9. · 15.25 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The Merlin/NF2 tumor suppressor restrains cell growth and tumorigenesis by controlling contact-dependent inhibition of proliferation. We have identified a tight-junction-associated protein complex comprising Merlin, Angiomotin, Patj, and Pals1. We demonstrate that Angiomotin functions downstream of Merlin and upstream of Rich1, a small GTPase Activating Protein, as a positive regulator of Rac1. Merlin, through competitive binding to Angiomotin, releases Rich1 from the Angiomotin-inhibitory complex, allowing Rich1 to inactivate Rac1, ultimately leading to attenuation of Rac1 and Ras-MAPK pathways. Patient-derived Merlin mutants show diminished binding capacities to Angiomotin and are unable to dissociate Rich1 from Angiomotin or inhibit MAPK signaling. Depletion of Angiomotin in Nf2(-/-) Schwann cells attenuates the Ras-MAPK signaling pathway, impedes cellular proliferation in vitro and tumorigenesis in vivo.
    Cancer cell 04/2011; 19(4):527-40. · 25.29 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Adipose tissue secretes proteins referred to as adipokines, many of which promote inflammation and disrupt glucose homeostasis. Here we show that secreted frizzled-related protein 5 (Sfrp5), a protein previously linked to the Wnt signaling pathway, is an anti-inflammatory adipokine whose expression is perturbed in models of obesity and type 2 diabetes. Sfrp5-deficient mice fed a high-calorie diet developed severe glucose intolerance and hepatic steatosis, and their adipose tissue showed an accumulation of activated macrophages that was associated with activation of the c-Jun N-terminal kinase signaling pathway. Adenovirus-mediated delivery of Sfrp5 to mouse models of obesity ameliorated glucose intolerance and hepatic steatosis. Thus, in the setting of obesity, Sfrp5 secretion by adipocytes exerts salutary effects on metabolic dysfunction by controlling inflammatory cells within adipose tissue.
    Science 07/2010; 329(5990):454-7. · 31.20 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Secreted frizzled-related protein 1 (Sfrp1) is highly expressed by stromal cells maintaining hematopoietic stem cells (HSCs). Sfrp1 loss in stromal cells increases production of hematopoietic progenitors, and in knockout mice, dysregulates hemostasis and increases Flk2- Cd34- Lin- Sca1+ Kit+ (LSK) cell numbers in bone marrow. Also, LSK and multipotent progenitors (MPPs) resided mainly in the G0/G1 phase of cell cycle, with an accompanying decrease in intracellular beta-catenin levels. Gene-expression studies showed a concomitant decrease Ccnd1 and Dkk1 in Cd34- LSK cells and increased expression of Pparg, Hes1, and Runx1 in MPP. Transplantation experiments showed no intrinsic effect of Sfrp1 loss on the number of HSCs or their ability to engraft irradiated recipients. In contrast, serial transplantations of wild-type HSCs into Sfrp1(-/-) mice show a progressive decrease of wild-type LSK and MPP numbers. Our results demonstrate that Sfrp1 is required to maintain HSC homeostasis through extrinsic regulation of beta-catenin.
    Cell stem cell 09/2009; 5(2):157-67. · 23.56 Impact Factor
  • Source
    Makoto Matsuyama, Shinichi Aizawa, Akihiko Shimono
    [show abstract] [hide abstract]
    ABSTRACT: Epithelial tubular morphogenesis leading to alteration of organ shape has important physiological consequences. However, little is known regarding the mechanisms that govern epithelial tube morphogenesis. Here, we show that inactivation of Sfrp1 and Sfrp2 leads to reduction in fore-stomach length in mouse embryos, which is enhanced in the presence of the Sfrp5 mutation. In the mono-cell layer of fore-stomach epithelium, cell division is normally oriented along the cephalocaudal axis; in contrast, orientation diverges in the Sfrps-deficient fore-stomach. Cell growth and apoptosis are not affected in the Sfrps-deficient fore-stomach epithelium. Similarly, cell division orientation in fore-stomach epithelium diverges as a result of inactivation of either Stbm/Vangl2, an Fz/PCP component, or Wnt5a. These observations indicate that the oriented cell division, which is controlled by the Fz/PCP pathway, is one of essential components in fore-stomach morphogenesis. Additionally, the small intestine epithelium of Sfrps compound mutants fails to maintain proper apicobasal polarity; the defect was also observed in Wnt5a-inactivated small intestine. In relation to these findings, Sfrp1 physically interacts with Wnt5a and inhibits Wnt5a signaling. We propose that Sfrp regulation of Wnt5a signaling controls oriented cell division and apicobasal polarity in the epithelium of developing gut.
    PLoS Genetics 04/2009; 5(3):e1000427. · 8.52 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Secreted frizzled-related proteins (Sfrps) are antagonists of WNT signalling implicated in a variety of biological processes. However, there are no reports of a direct role for Sfrps in embryonic organogenesis in mammals. Using in vivo loss-of-function studies we report here for the first time a redundant role for Sfrp1 and Sfrp2 in embryonic sexual development of the mouse. At 16.5 dpc, male embryos lacking both genes exhibit multiple defects in gonad morphology, reproductive tract maturation and gonad positioning. Abnormal positioning of the testis appears to be due to failed gubernaculum development and an unusually close association between the cranial end of the reproductive tract and the kidney. The testes of double homozygotes are smaller than controls, contain fewer cords from the earliest stages, but still express Insl3, which encodes the hormone required for gubernacular masculinisation. Lgr8, which encodes the Insl3 receptor, is also expressed in the mutant gubernaculum, suggesting that Sfrp1/Sfrp2 signalling is not required for expression of the ligand or receptor that controls transabdominal testicular descent. Similarities between the abnormalities of embryonic sexual development in Sfrp1(-/-)Sfrp2(-/-) embryos with those exhibited by the Looptail and Wnt5a mutants suggest that disrupted non-canonical Wnt signalling may cause these defects.
    Developmental Biology 01/2009; 326(2):273-84. · 3.87 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The secreted frizzled-related protein gene family encodes proteins that regulate Wnt signaling. Msx1 in situ hybridization of 9.5 days post coitus mouse embryos showing normal neural tube development in an Sfrp1; Sfrp2 double mutant (left) but severe neural tube defects in a Looptail (Lp/+); Sfrp1; Sfrp2 triple mutant (right). These findings suggest that Sfrps regulate the Wnt planar cell polarity pathway. See Satoh et al. in this issue.
    genesis 01/2009; 46(2):spcone. · 2.58 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: How an organ develops its characteristic shape is a major issue. This is particularly critical for the eye lens as its function depends on having appropriately ordered three-dimensional cellular architecture. Recent in vitro studies indicate that Wnt signaling plays key roles in regulating morphological events in FGF-induced fiber cell differentiation in the mammalian lens. To further investigate this the Wnt signaling antagonist, secreted frizzled-related protein 2 (Sfrp2), was overexpressed in lens fiber cells of transgenic mice. In these mice fiber cell elongation was attenuated and individual fibers exhibited irregular shapes and consequently did not align or pack regularly; microtubules, microfilaments and intermediate filaments were clearly disordered in these fibers. Furthermore, a striking feature of transgenic lenses was that fibers did not develop the convex curvature typically seen in normal lenses. This appears to be related to a lack of protrusive processes that are required for directed migratory activity at their apical and basal tips as well as for the formation of interlocking processes along their lateral margins. Components of the Wnt/Planar Cell Polarity (PCP) pathway were downregulated or inhibited. Taken together this supports a role for Wnt/PCP signaling in orchestrating the complex organization and dynamics of the fiber cell cytoskeleton.
    Developmental Biology 10/2008; 324(1):161-76. · 3.87 Impact Factor
  • genesis 01/2008; 46(2):92-103. · 2.58 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The development of the embryonic vascular system into a highly ordered network requires precise control over the migration and branching of endothelial cells (ECs). We have previously identified angiomotin (Amot) as a receptor for the angiogenesis inhibitor angiostatin. Furthermore, DNA vaccination targeting Amot inhibits angiogenesis and tumor growth. However, little is known regarding the role of Amot in physiological angiogenesis. We therefore investigated the role of Amot in embryonic neovascularization during zebrafish and mouse embryogenesis. Here we report that knockdown of Amot in zebrafish reduced the number of filopodia of endothelial tip cells and severely impaired the migration of intersegmental vessels. We further show that 75% of Amot knockout mice die between embryonic day 11 (E11) and E11.5 and exhibit severe vascular insufficiency in the intersomitic region as well as dilated vessels in the brain. Furthermore, using ECs differentiated from embryonic stem (ES) cells, we demonstrate that Amot-deficient cells have intact response to vascular endothelial growth factor (VEGF) in regard to differentiation and proliferation. However, the chemotactic response to VEGF was abolished in Amot-deficient cells. We provide evidence that Amot is important for endothelial polarization during migration and that Amot controls Rac1 activity in endothelial and epithelial cells. Our data demonstrate a critical role for Amot during vascular patterning and endothelial polarization.
    Genes & Development 09/2007; 21(16):2055-68. · 12.44 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Regulation of Wnt signaling is essential for embryonic patterning. Sfrps are secreted Wnt antagonists that directly interact with the Wnt ligand to inhibit signaling. Here, we show that Sfrp1 and Sfrp2 are required for anteroposterior (AP) axis elongation and somitogenesis in the thoracic region during mouse embryogenesis. Double homozygous mutations in Sfrp1 and Sfrp2 lead to severe shortening of the thoracic region. By contrast, a homozygous mutation in one or the other exerts no effect on embryogenesis, indicating that Sfrp1 and Sfrp2 are functionally redundant. The defect of a shortened thoracic region appears to be the consequence of AP axis reduction and incomplete somite segmentation. The reduction in the AP axis is partially due to abnormalities in cell migration of pre-somitic mesoderm from the end of gastrulation. Aberrant somite segmentation is associated with altered oscillations of Notch signaling, as evidenced by abnormal Lfng and Hes7 expression during somitogenesis in the thoracic region. This study suggests that Wnt regulation by Sfrp1 and Sfrp2 is required for embryonic patterning.
    Development 04/2006; 133(6):989-99. · 6.21 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Recent loss-of-function and gain-of-function studies have revealed that transcription factor Sox9 is required for testis formation by governing Sertoli cell differentiation, and thereafter regulating transcription of Sertoli marker genes. In the present study, we identified a novel isoform of Vinexin, which is expressed in somatic cells but not germ cells of sexually indifferent stages of fetal gonads. After the sex is determined, the expression continues in testicular Sertoli cells. Immunohistochemical analyses with a specific antibody to Vinexin indicated that Vinexin gamma is localized in the cytoplasm. Functional studies with C3H10T1/2 cells showed that Vinexin gamma acted as a scaffold protein to activate MEK and ERK through interaction with c-Raf and ERK. Ultimately, Sox9 transcription was induced by Vinexin gamma. This up-regulation of Sox9 expression disappeared when the cells were treated with a specific MEK inhibitor, U0126. To determine the role of Vinexin gamma during gonad formation, the gene was disrupted by targeted mutagenesis. The phenotype displayed by the mice indicated that ERK activation was decreased in the Vinexin gamma(-/-) XY gonads, and Sox9 expression was down-regulated. Thus, Vinexin gamma seems to be implicated in regulation of Sox9 gene expression by modulating MAPK cascade in mouse fetal gonads.
    Genes to Cells 06/2005; 10(5):421-34. · 2.73 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Previous work has indicated that N-myc expression occurs widely in the developing central nervous system, but its level changes dynamically with region- and stage-specificities. We show in the present report that in the developing spinal cord of the mouse, N-myc protein expression takes place in the ventricular zone and reaches its maximum at the outermost layer, but is extinct in the intermediate zone, indicating that N-myc protein is not expressed in mature neurons. We examined the effect of forced, persistent N-myc expression in development of the spinal cord in order to understand the functional significance of N-myc down-regulation. We made embryonic stem (ES) cell lines that constitutively expressed N-myc at a high level, then produced mouse embryo chimeras with a high contribution of the ES cells. The majority of the chimeras developed to day 12 with normal gross morphology, but in these chimeras neuronal differentiation in the spinal cord was perturbed at the histological level. Intermediate zones and ventral horns were formed, but the expression of N-CAM and neurofilaments was diminished. Chimeras using β-galactosidase-expressing recipient embryos indicated that inhibition of the neuronal differentiation was a cell-autonomous effect of persistent N-myc expression. These observations indicate that N-myc down-regulation in individual cells is required for full differentiation of neurons.
    Embryologia 10/2003; 38(6):707 - 716. · 2.21 Impact Factor

Publication Stats

1k Citations
272.40 Total Impact Points


  • 2012
    • Aichi Cancer Center
      Ōsaka, Ōsaka, Japan
  • 2009
    • National University of Singapore
      • Center for Life Sciences (CeLS)
      Singapore, Singapore
  • 2003
    • Osaka University
      • Division of Cellular and Molecular Biology
      Ibaraki, Osaka-fu, Japan
  • 1999–2003
    • University of Texas MD Anderson Cancer Center
      • Human and Molecular Genetics
      Houston, TX, United States
  • 1991–1993
    • Nagoya University
      • Division of Cell Science
      Nagoya-shi, Aichi-ken, Japan