Hiroaki Yamamoto

Nagahama Institute of Bio-Science and Technology, Нагахама, Shiga Prefecture, Japan

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Publications (59)173.35 Total impact

  • Koji Ohba · Kazuhisa Takeda · Hiroaki Yamamoto · Shigeki Shibahara
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    ABSTRACT: Microphthalmia-associated transcription factor (Mitf) is a key regulator for differentiation of the neural crest-derived melanocytes. Mitf consists of multiple isoforms, including melanocyte-specific Mitf-M and widely expressed Mitf-A and Mitf-H. Mitf mRNAs are also expressed in the brain, although the identity of Mitf-expressing cells remains unknown. We therefore aimed to identify Mitf-expressing cells in the brain. By the immunohistochemical analysis, we detected Mitf-expressing cells only in the olfactory bulb of the C57BL/6 mouse. The Mitf-expressing cells were then identified as projection neurons, mitral cells and tufted cells, both of which receive the signal from the olfactory neurons and transmit the information to the olfactory cortex. Real-time RT-PCR analysis showed the expression level of Mitf-M mRNA was comparable to the expression levels of Mitf-A and Mitf-H mRNAs in the olfactory bulb. We then analyzed Mitf-expressing neurons in the olfactory bulb of the homozygous black-eyed white (Mitf(mi-bw) ) mouse that is characterized by the lack of melanocytes. Mitf was expressed in mitral cells and tufted cells in the olfactory bulb of the Mitf(mi-bw) mouse, thereby excluding the contribution of melanocytes to the detected expression of Mitf-M. In conclusion, Mitf, including Mitf-M, is expressed in mitral cells and tufted cells of the olfactory bulb.
    No preview · Article · Nov 2015 · Genes to Cells
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    ABSTRACT: Microphthalmia-associated transcription factor (Mitf) is required for the differentiation of melanoblasts of the neural crest origin. The mouse homozygous for the black-eyed white (Mitf(mi-bw) ) allele is characterized by white-coat color and deafness with black eye, due to the loss of melanoblasts during embryonic development. The Mitf(mi-bw) allele carries an insertion of long interspersed element-1 (L1) in intron 3 of the Mitf gene, which may cause the deficiency of melanocyte-specific Mitf-M. Here, we show that the L1 insertion results in the generation of alternatively spliced Mitf-M mRNA species, such as Mitf-M mRNA lacking exon 3, exon 4 or both exons 3 and 4, each of which encodes Mitf-M protein with an internal deletion. Transient expression assays showed the loss of or reduction in function of each aberrant Mitf-M protein and the dominant negative effect of Mitf-M lacking exon 4 that encodes an activation domain. Thus, the L1 insertion may decrease the expression level of functional Mitf-M. Importantly, Mitf-M mRNA is expressed in the wild-type mouse brain, with the highest expression level in the hypothalamus. Likewise, aberrant Mitf-M mRNAs are expressed in the bw mouse brain. The bw mice show the altered neurobehavior under a stressful environment, suggesting the role of Mitf-M in sensory perception.
    No preview · Article · Dec 2013 · Genes to Cells
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    ABSTRACT: Background Patent ductus arteriosus is a life-threatening condition frequent in premature newborns but also present in some term infants. Current mouse models of this malformation generally lead to perinatal death, not reproducing the full phenotypic spectrum in humans, in whom genetic inheritance appears complex. The ductus arteriosus (DA), a temporary fetal vessel that bypasses the lungs by shunting the aortic arch to the pulmonary artery, is constituted by smooth muscle cells of distinct origins (SMC1 and SMC2) and many fewer melanocytes. To understand novel mechanisms preventing DA closure at birth, we evaluated the importance of cell fate specification in SMC that form the DA during embryonic development. Upon specific Tyr::Cre-driven activation of Wnt/β-catenin signaling at the time of cell fate specification, melanocytes replaced the SMC2 population of the DA, suggesting that SMC2 and melanocytes have a common precursor. The number of SMC1 in the DA remained similar to that in controls, but insufficient to allow full DA closure at birth. Thus, there was no cellular compensation by SMC1 for the loss of SMC2. Mice in which only melanocytes were genetically ablated after specification from their potential common precursor with SMC2, demonstrated that differentiated melanocytes themselves do not affect DA closure. Loss of the SMC2 population, independent of the presence of melanocytes, is therefore a cause of patent ductus arteriosus and premature death in the first months of life. Our results indicate that patent ductus arteriosus can result from the insufficient differentiation, proliferation, or contractility of a specific smooth muscle subpopulation that shares a common neural crest precursor with cardiovascular melanocytes.
    Full-text · Article · Jan 2013 · PLoS ONE
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    ABSTRACT: The retinal pigment epithelium (RPE) shares its developmental origin with the neural retina (NR). When RPE development is disrupted, cells in the presumptive RPE region abnormally differentiate into NR-like cells. Therefore, the prevention of NR differentiation in the presumptive RPE area seems to be essential for regionalizing the RPE during eye development. However, its molecular mechanisms are not fully understood. In this study, we conducted a functional inhibition of a transcription factor Otx2, which is required for RPE development, using early chick embryos. The functional inhibition of Otx2 in chick eyes, using a recombinant gene encoding a dominant negative form of Otx2, caused the outer layer of the optic cup (the region forming the RPE, when embryos normally develop) to abnormally form an ectopic NR. In that ectopic NR, the characteristics of the RPE did not appear and NR markers were ectopically expressed. Intriguingly, the repression of Otx2 function also caused the ectopic expression of Fgf8 and Sox2 in the outer layer of the optic cup (the presumptive RPE region of normally developing eyes). These two factors are known to be capable of inducing NR cell differentiation in the presumptive RPE region, and are not expressed in the normally developing RPE region. Here, we suggest that Otx2 prevents the presumptive RPE region from forming the NR by repressing the expression of both Fgf8 and Sox2 which induce the NR cell fate.
    Full-text · Article · Nov 2012 · PLoS ONE
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    ABSTRACT: Microphthalmia-associated transcription factor (Mitf) is a regulator for differentiation of melanoblasts that are derived from the neural crest. The mouse homozygous for the black-eyed white (Mitf(mi-bw)) allele is characterized by the white coat color and deafness, with black eye that is associated with the lack of melanocytes in skin and inner ear. The Mitf(mi-bw) mutation is an insertion of the LINE1 retrotransposable element into intron 3 of the Mitf gene that causes the selective deficiency of the melanocyte-specific Mitf isoform, Mitf-M. Here, we show the expression of Mitf-M mRNA in the trunk region of the homozygous Mitf(mi-bw)(bw) mouse at embryonic days (E) 11.5 and E12.5, but Mitf-M mRNA is undetectable at E13.5. In addition, using bw mouse that carries the lacZ transgene under the control of a melanoblast-specific promoter, we show that the number of migrating melanoblasts in bw embryos was less than 10% of that in control embryos at E11.5 and E12.5, and melanoblasts disappear by E13.5. The loss of melanoblasts in bw embryos was probably caused by apoptosis. Finally, forced expression of Mitf-M in the cultured neural tube of bw embryos ensured the differentiation of melanoblasts. Therefore, the correct dose of Mitf-M is required for the normal development of melanoblasts.
    Full-text · Article · May 2012 · Genes to Cells
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    ABSTRACT: Melanoblasts are derived from neural crest cells (NCCs) and are the only NCCs that migrate through the dorsolateral pathway. However, how melanoblasts evolved to migrate through a pathway different from other NCCs is still unclear, because little is known about common molecular mechanisms of melanoblast migration that are conserved between species. Endothelin receptor B2 (Ednrb2) is required for avian melanoblasts to enter the dorsolateral pathway. Here, we show that Endothelin-3 (ET3)/Ednrb2 signaling is also required for melanoblast migration in Xenopus laevis, although they migrate through the ventral pathway. In Xenopus, Ednrb2 is expressed by melanoblasts from pre-migration stages and ET3 is expressed around their destinations, suggesting that ET3/Ednrb2 signaling may determine melanophore localization. Furthermore, melanoblast migration is interrupted by aberrant ET3/Ednrb2 signaling in vivo and their invasive ability is enhanced by ET3 in vitro. Our results suggest that ET3/Ednrb2 signaling is required for melanoblast migration in Ednrb2 gene-conserved animals.
    Preview · Article · Jun 2011 · Developmental Dynamics
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    ABSTRACT: The guppy (Poecilia reticulata) is an important model organism for studying sexual selection; male guppies have complex and conspicuous pigmentation, and female guppies exhibit preferences for males with specific color spots. Understanding the genetic basis underlying pigmentation variation in the guppy is important for exploring the factors causing the maintenance of color polymorphism in wild populations. We focused on the melanic black pigmentation of guppies, and examined genetic variations in the melanocortin 1 receptor (MC1R) gene because variation in this gene is known to contribute to polymorphism of melanin pigmentation in several animal species. The complete coding sequence of the guppy MC1R gene was determined, and two different MC1R alleles (963 and 969 bp) were found in wild populations. Ornamental strain guppies with a 963-bp MC1R tended to show less black pigmentation than those with a 969-bp MC1R, although the association between MC1R genotype and black pigmentation disappeared in the F2 offspring. The guppy MC1R gene showed variation in the five wild Trinidadian populations we examined, and these populations also differed in terms of allele frequencies. We identified a significant association between black pigmentation and MC1R genotype in fish obtained from aquarium shops. However, the results from F2 families suggest that there are other genes that modify the effects of the MC1R gene.
    Full-text · Article · Feb 2011 · BMC Research Notes
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    ABSTRACT: Previously, we have shown that phenyl hydroquinone, a hepatic metabolite of the Ames test-negative carcinogen o-phenylphenol, efficiently induced aneuploidy in Saccharomyces cerevisiae by arresting the cell cycle at the G2/M transition as a result of the activation of the Hog1 (p38 MAPK homolog)-Swe1 (Wee1 homolog) pathway. In this experiment, we examined the aneuploidy forming effects of hydroquinone, a benzene metabolite, since both phenyl hydroquinone and hydroquinone are Ames-test negative carcinogens and share similar molecular structures. As was seen in phenyl hydroquinone, hydroquinone induced aneuploidy in yeast by delaying the cell cycle at the G2/M transition. Deficiencies in SWE1 and HOG1 abolished the hydroquinone-induced delay at the G2/M transition and aneuploidy formation. Furthermore, Hog1 was phosphorylated by hydroquinone, which may stabilize Swe1. These data indicate that the hydroquinone-induced G2/M transition checkpoint, which is activated by the Hog1-Swe1 pathway, plays a role in the formation of aneuploidy.
    No preview · Article · May 2010 · Journal of Radiation Research
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    ABSTRACT: In eukaryotes, together with the Mre11/Rad50/Xrs2 (or Nbs1) complex, a family of related protein kinases (the ATM family) is involved in checkpoint activation in response to DNA double-strand breaks. In Saccharomyces cerevisiae, two members of this family, MEC1 and TEL1, have functionally redundant roles in DNA damage repair. Strains with mutations in their mec1 as well as mre11 genes are very sensitive to DNA damaging agents, show defective induction of damage-induced cell-cycle checkpoints, and defective damage-induced homologous recombination. However, the fact that both the mec1Delta and mre11Delta strains exhibit the spontaneous hyper-recombination phenotype is paradoxical in light of the homologous recombination defects in these strains. In this study, we constructed yeast mec1, tel1, and mre11 null mutations and characterized their genome stability properties. Spontaneous and methylmethane sulfonate (MMS)-induced point mutations, base-substitutions, and frameshifts occurred to an almost equal extent in the wild-type, mec1Delta, tel1Delta, and mre11Delta strains. Thus, Mec1, Tel1, and Mre11 do not play roles in the point mutation response. We then found that the mec1Delta, mre11Delta, and mec1Delta tel1Delta strains demonstrated increased rates of spontaneous loss of heterozygosity (LOH), which includes crossover, gene conversion, and chromosome loss, compared with the wild-type strain. In the tel1Delta strain, the rate of spontaneous LOH was as low as that in the wild-type strain. Finally, no induction of LOH by MMS was observed in the mec1Delta, mre11Delta, or mec1Delta tel1Delta strain; however, it was detected in the wild-type and tel1Delta strains upon exposure to MMS. The elevated level of spontaneous LOH but not MMS-induced LOH in the mec1Delta, mre11Delta, and mec1Delta tel1Delta strains suggests the presence of high levels of spontaneous recombinogenic DNA damage, which differs from the damage induced by MMS treatment, in these strains.
    No preview · Article · Feb 2010 · Genes & Genetic Systems
  • Shigeyuki Uehara · Akiha Kawasaki · Hiroaki Yamamoto

    No preview · Article · Oct 2009 · Pigment Cell & Melanoma Research
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    Akiha Kawasaki · Mayuko Kumasaka · Hiroaki Yamamoto

    Preview · Article · Aug 2009 · Mechanisms of Development
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    ABSTRACT: Mitf has been reported to play a crucial role in regulating the differentiation of pigment cells in homeothermal animals, i.e. the melanocytes and the retinal pigment epithelium (RPE). However, less is known about the functions of Mitf in the developing RPE. To elucidate such functions, we introduced wild-type and dominant-negative Mitf expression vectors into chick optic vesicles by electroporation. Over-expression of wild-type Mitf altered neural retina cells to become RPE-like and repressed the expression of neural retina markers in vivo. In contrast, dominant-negative Mitf inhibited pigmentation in the RPE. The percentage of BrdU-positive cells decreased during normal RPE development, which was followed by Mitf protein expression. The percentage of BrdU-positive cells decreased in the wild-type Mitf-transfected neural retina, but increased in the dominant-negative Mitf-transfected RPE. p27(kip1), one of the cyclin-dependent kinase inhibitors, begins to be expressed in the proximal region of the RPE at stage 16. Transfection of wild-type Mitf induced expression of p27(kip1), while transfection of dominant-negative Mitf inhibited p27(kip1) expression. We found that Mitf was associated with the endogenous p27(kip1) 5' flanking region. These results demonstrate for the first time "in vivo" that Mitf uniquely regulates both differentiation and cell proliferation in the developing RPE.
    Full-text · Article · Feb 2009 · Developmental Biology
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    ABSTRACT: Mammalian pigment cells produce melanin as the main pigment. Melanocytes, one of the two types of mammalian pigment cells, differentiate from the neural crest and migrate to a variety of organs during development. Melanocytes exist not only in the skin but also in other sites such as the cochlea where they are essential for hearing. Mitf(mi-bw) is one of the known recessive alleles of the mouse microphthalmia-associated transcription factor (Mitf) locus, which is essential for the development of pigment cells. Homozygous Mitf(mi-bw)/Mitf(mi-bw) mice have a completely white coat with black eyes and are deaf due to the lack of melanocytes. By comparing gene expression profiles in cochleae of wild-type and Mitf(mi-bw)/Mitf(mi-bw) mice, we now demonstrate the specific expression of glutathione S-transferase alpha 4 (Gsta4) in the stria vascularis. Gsta4 encodes one of the cytosolic glutathione S-transferases (GSTs) which participate in detoxification processes of many tissues. This gene is specifically expressed in intermediate cells of the stria vascularis, suggesting a novel function for cochlear melanocytes. Moreover, among mammalian pigment cells, expression of Gsta4 was restricted to cochlear melanocytes, suggesting that melanocytes in various tissues differentiate from one another depending on their location.
    No preview · Article · Nov 2008 · Pigment Cell & Melanoma Research
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    ABSTRACT: Mitf is a transcription factor of the basic/helix-loop-helix/leucine-zipper family which is indispensable for development of melanocytes and the retinal pigment epithelium. Our previous work using Xenopus laevis as a model system suggested that Mitf regulates melanosome dispersal in vivo though whether this was via melanosome transport or melanophore dendricity was not obvious. To better understand the role of Mitf, we have now characterized neural tube cultures from wild-type Mitf-injected or a dominant-negative Mitf-injected embryos and compared them with controls. In vitro, lower levels of Mitf activity induced less dendritic melanophores with aggregated melanosomes, whereas melanophores overexpressing Mitf had an extensive dendritic morphology with dispersed melanosomes. Moreover, immunorfluoresence assays reveal that expression of a dominant-negative Mitf leads to decreased Rab27a expression. These results suggest that Mitf is involved in the regulation of melanosome transport and the level of dendricity in melanophores.
    No preview · Article · Mar 2008 · Pigment Cell & Melanoma Research
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    ABSTRACT: Microphthalmia-associated transcription factor (Mitf) is responsible for differentiation of melanocytes, and a recessive Mitf mutant, black-eyed white (bw) mouse, is characterized by the lack of melanocytes in the skin and inner ear. To search for the hitherto unknown roles of melanocytes, we analysed the ventilatory responses of unanaesthetized bw mice by whole body plethysmography. During air breathing, bw mice showed lower breathing frequency and larger tidal volume, compared with age-matched wild-type mice, although there was no difference in the minute ventilation. Importantly, bw mice present normal haematocrit values and red blood cell counts. We next measured the immediate ventilatory responses to acute hypoxia (10% O2) and to hyperoxic hypercapnia (10% CO2). Hypoxic and hypercapnic ventilatory responses represent the functions of the chemoreceptors in the carotid body and the brainstem, respectively. The bw mice retain the peripheral hypoxic and central hypercapnic sensing functions, but exhibited augmented ventilatory responses to both hypoxia and hypercapnia. Unexpectedly, RT-PCR analysis has shown the expression of melanocyte-specific Mitf mRNA in the brain of bw mice, suggesting the presence of leptomeningeal melanocytes. These findings suggest a functional link between skin melanocytes and the central respiratory controller that generates respiratory rhythm and pattern.
    No preview · Article · Apr 2007 · Journal of Biochemistry
  • TAKUJI TAKEUCHI · HIROAKI YAMAMOTO
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    ABSTRACT: Melanocytes originate from the neural crest in vertebrates and migrate to the body surface where they differentiate into functional cells. Genes involved in melanocyte differentiation can be classified into two groups. One of them consists of the functional genes that control proteins specific to the function of the melanocyte. As the representative gene of this category, albino (c) locus in the mouse is considered to control tyrosinase, the key enzyme in melanogenesis. cDNA for mouse tyrosinase has been cloned and sequenced. The cDNA can be used to detect tyrosinase mRNA synthesized during melanocyte differentiation. On the other hand, genes such as brown (b) or pink-eyed dilution (p) have been assumed to control melanosome proteins. The other category consists of genes that regulate the expression of these functional genes directly or indirectly. In the mouse, so-called white-spotting genes and genes of the agouti series are considered to fall into this category. Based on the fact that mutations at the white-spotting loci result in the absence of melanocytes in a particular area of skin, it is assumed that some of these loci control the factors that promote either differentiation or migration of melanoblasts and are candidates for the classic regulator genes Genes at the agouti (a) locus in the mouse determine the type of melanin synthesized in hair follicle melanocytes, that is eumelanin or pheomelanin. An interesting feature of this locus is that the site of gene action is not within the melanocytes but in the cells surrounding them. The results of our study indicate that the gene product of the a-locus interacts with α-MSH at the α-MSH receptor site, regulates the cellular cAMP level via a signal transduction system and, in turn, determines the type of melanin synthesized in the cells.
    No preview · Article · Jul 2006 · Pigment Cell Research
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    ABSTRACT: Virally introduced mouse tyrosinase expression was checked both in vitro and in vivo in chicken cells and tissues. The results indicate that a constitutive promoter is able to express mouse tyrosinase in a variety of cells and tissues both in vitro and in vivo. Tyrosinase expression is marked by pigment production in situ, which is visible at macroscopic as well as microscopic levels without the use of substrates. It is concluded that tyrosinase can be a valuable marker for tracking gene insertion since it is spontaneously expressed. The expression of tyrosinase in some cells and tissues has a detrimental effect, however, and should be controlled by tissue-specific promoters.
    No preview · Article · Jul 2006 · Pigment Cell Research
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    ABSTRACT: Microphthalmia-associated transcription factor (MITF) is responsible for differentiation of melanocytes. A recessive MITF mutant, black-eyed white Mitf(mi-bw) mouse, is characterized by white coat color and deafness, due to the lack of melanocytes in the skin and inner ears. By cDNA microarray analysis, we have identified lipocalin-type prostaglandin D synthase (L-PGDS), whose mRNA is undetectable in the homozygous Mitf(mi-bw) skin. Immunohistochemical analysis of wild-type mice identified the specific expression of L-PGDS in follicular melanocytes. L-PGDS mRNA is expressed in B16 mouse melanoma cells, but undetectable in human melanoma cell lines. RNA interference analysis against MITF suggests that L-PGDS expression is dependent on MITF in B16 melanoma cells. Furthermore, we have provided evidence that MITF is involved in the melanocyte lineage-specific transcription of the mouse L-PGDS gene. Thus, L-PGDS represents a newly identified melanocyte marker. MITF may modulate the production of prostaglandin D(2) by activating the L-PGDS gene in melanocytes.
    Preview · Article · Feb 2006 · Biochemical and Biophysical Research Communications
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    ABSTRACT: Mitf is a central regulator of pigment cell development that is essential for the normal development of the melanocyte and retinal pigment epithelium (RPE) lineages. To understand better the role of Mitf, we have used the Xenopus laevis experimental system to allow a rapid examination of the role of Mitf in vivo. Here, we report the function of XlMitfalpha-M on melanophore development and melanization compared with that of Slug that is expressed in neural crest cells. Overexpression of XlMitfalpha-M led to an increase in melanophores that was partly contributed by an increase in Slug-positive cells, indicating that XlMitfalpha-M is a key regulator of melanocyte/melanophore development and melanization. Moreover, overexpression of a dominant-negative form of XlMitfalpha led to a decrease in the number of melanophores and induced abnormal melanoblast migration. We also observed an induction of ectopic RPE and extended RPE by overexpression of XlMitfalpha-M and possible interactions between XlMitfalpha and several eye-related genes essential for normal eye development.
    Full-text · Article · Nov 2005 · Developmental Dynamics
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    ABSTRACT: Solitary ascidian tadpole larvae develop two types of black pigment cells in the major sensory organs of the brain. Such pigment cells have been demonstrated to express the melanogenic genes, tyrosinase and Tyrp/TRP (tyrosinase-related protein). To understand the genetic and developmental mechanisms underlying the differentiation of chordate pigment cells, we examined the function of the promoter region of Tyrp/TRP gene, an ascidian (Halocynthia roretzi) tyrosinase family gene. The expression of the gene in pigment cell lineage starts at the early-mid gastrula stages. To identify the transcriptional regulatory region of the gene allowing cell-type-specific expression, a deletion series of the HrTyrp 5' flanking region fused to a lacZ reporter gene was constructed and microinjected into ascidian fertilized eggs. The region of 73 bp in HrTyrp was identified as sufficient for expression in pigment cell-precursors of tailbud stage embryos. It is noteworthy that there is no M-box element highly conserved in the promoters for vertebrate tyrosinase family genes such as tyrosinase, Tyrp1/TRP-1 and Tyrp2/TRP-2 (Dct). Although the regulatory system of ascidian pigment-cell development is likely to contain most factors critical to vertebrate pigment-cell development, there might be critical differences in the mode of regulation, such as the developmental timing of interactions of factors, proteins and genes, involved in pigment cell differentiation and pigmentation.
    No preview · Article · Jun 2004 · Gene

Publication Stats

1k Citations
173.35 Total Impact Points

Institutions

  • 2011-2013
    • Nagahama Institute of Bio-Science and Technology
      Нагахама, Shiga Prefecture, Japan
  • 1984-2011
    • Tohoku University
      • • Department of Developmental Biology and Neuroscience
      • • Graduate School of Life Sciences
      • • Biological Institute
      Sendai, Kagoshima, Japan
  • 2002
    • Osaka University
      • Department of Earth and Space Science
      Suika, Ōsaka, Japan
  • 1987
    • Tokyo Metropolitan University
      • Department of Chemistry
      Edo, Tōkyō, Japan