Haruhiko Yamamoto’s research while affiliated with University of the Ryukyus and other places

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Publications (13)


The Proto-oncogene BCL6 Promotes Survival of Olfactory Sensory Neurons
  • Article

May 2010

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17 Reads

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12 Citations

Developmental Neurobiology

Joji M Otaki

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Masahiko Hatano

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Rie Matayoshi

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[...]

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Haruhiko Yamamoto

For the mammalian olfactory epithelium to continually detect odorant, neuronal survival, apoptosis, and regeneration must be coordinated. Here, we showed that the proto-oncogene BCL6, which encodes a transcriptional repressor required for lymphocyte terminal differentiation, contributes to the survival of olfactory sensory neurons (OSNs). In the olfactory epithelia of the BCL6 null mutant mice, many OSNs were positive for both OMP and GAP43. The epithelium was relatively thinner, showing many apoptotic signals. These characters were phenotypically similar to those of the wild-type mice treated with nasal lectin irrigation, which acutely induces apoptosis of OSNs. Odorant receptors were expressed normally in the epithelia of the mutant mice, and their overall expression profile based on DNA microarray analyses was roughly similar to that of the apoptosis-induced olfactory epithelia of the wild-type mice. Experimental increase of BCL6 together with green fluorescent protein in OSNs using adenovirus-mediated gene transfer made the epifluorescence last longer than the control fluorescence without exogenous BCL6 after the nasal lectin irrigation, indicating that BCL6 made the infected neurons survive longer. We conclude that BCL6 plays an active role in the survival of OSNs as an anti-apoptotic factor and confers immature OSNs enough time to fully differentiate into mature ones.


Secondary Structure Characterization Based on Amino Acid Composition and Availability in Proteins

March 2010

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101 Reads

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38 Citations

Journal of Chemical Information and Modeling

The importance of thorough analyses of the secondary structures in proteins as basic structural units cannot be overemphasized. Although recent computational methods have achieved reasonably high accuracy for predicting secondary structures from amino acid sequences, a simple and fundamental empirical approach to characterize the amino acid composition of secondary structures was performed mainly in 1970s, with a small number of analyzed structures. To extend this classical approach using a large number of analyzed structures, here we characterized the amino acid sequences of secondary structures (12 154 alpha-helix units, 4592 3(10)-helix units, 16 787 beta-strand units, and 30 811 "other" units), using the representative three-dimensional protein structure records (1641 protein chains) from the Protein Data Bank. We first examined the length and the amino acid compositions of secondary structures, including rank order differences and assignment relationships among amino acids. These compositional results were largely, but not entirely, consistent with the previous studies. In addition, we examined the frequency of 400 amino acid doublets and 8000 triplets in secondary structures based on their relative counts, termed the availability. We identified not only some triplets that were specific to a certain secondary structure but also so-called zero-count triplets, which did not occur in a given secondary structure at all, even though they were probabilistically predicted to occur several times. Taken together, the present study revealed essential features of secondary structures and suggests potential applications in the secondary structure prediction and the functional design of protein sequences.


Potential implications of availability of short amino acid sequences in proteins: An old and new approach to protein decoding and design

February 2008

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40 Reads

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17 Citations

Biotechnology Annual Review

Three-dimensional structure of a protein molecule is primarily determined by its amino acid sequence, and thus the elucidation of general rules embedded in amino acid sequences is of great importance in protein science and engineering. To extract valuable information from sequences, we propose an analytical method in which a protein sequence is considered to be constructed by serial superimpositions of short amino acid sequences of n amino acid sets, especially triplets (3-aa sets). Using the comprehensive nonredundant protein database, we first examined "availability" of all possible combinatorial sets of 8,000 triplet species. Availability score was mathematically defined as an indicator for the relative "preference" or "avoidance" for a given short constituent sequence to be used in protein chain. Availability scores of real proteins were clearly biased against those of randomly generated proteins. We found many triplet species that occurred in the database more than expected or less than expected. Such bias was extended to longer sets, and we found that some species of pentats (5-aa sets) that occurred reasonably frequently in the randomly generated protein population did not occur at all in any real proteins known today. Availability score was dependent on species, potentially serving as a phylogenetic indicator. Furthermore, we suggest possibilities of various biotechnological applications of characteristic short sequences such as human-specific and pathogen-specific short sequences obtained from availability analysis. Availability score was also dependent on secondary structures, potentially serving as a structural indicator. Availability analysis on triplets may be combined with a comprehensive data collection on the varphi and psi peptide-bond angles of the amino acid at the center of each triplet, i.e., a collection of Ramachandran plots for each triplet. These triplet characters, together with other physicochemical data, will provide us with basic information between protein sequence and structure, by which structure prediction and engineering may be greatly facilitated. Availability analysis may also be useful in identifying word processing units in amino acid sequences based on an analogy to natural languages. Together with other approaches, availability analysis will elucidate general rules hidden in the primary sequences and eventually contributes to rebuilding the paradigm of protein science.


Alignment-Free Classification of G-Protein-Coupled Receptors Using Self-Organizing Maps

August 2006

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10 Reads

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25 Citations

Journal of Chemical Information and Modeling

Proteins are classified mainly on the basis of alignments of amino acid sequences. Drug discovery processes based on pharmacologically important proteins such as G-protein-coupled receptors (GPCRs) may be facilitated if more information is extracted directly from the primary sequences. Here, we investigate an alignment-free approach to protein classification using self-organizing maps (SOMs), a kind of artificial neural network, which needs only primary sequences of proteins and determines their relative locations in a two-dimensional lattice of neurons through an adaptive process. We first showed that a set of 1397 aligned samples of Class A GPCRs can be classified by our SOM program into 15 conventional categories with 99.2% accuracy. Similarly, a nonaligned raw sequence data set of 4116 samples was categorized into 15 conventional families with 97.8% accuracy in a cross-validation test. Orphan GPCRs were also classified appropriately using the result of the SOM learning. A supposedly diverse family of olfactory receptors formed the most distinctive cluster in the map, whereas amine and peptide families exhibited diffuse distributions. A feature of this kind in the map can be interpreted to reflect hierarchical family composition. Interestingly, some orphan receptors that were categorized as olfactory were somatosensory chemoreceptors. These results suggest the applicability and potential of the SOM program to classification prediction and knowledge discovery from protein sequences.



The proto-oncogene BCL-6 is expressed in olfactory sensory neurons

November 2005

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22 Reads

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12 Citations

Neuroscience Research

Mammalian olfactory sensory neurons harbor a large repertoire of odorant receptors. Yet, each cell chooses a single odorant receptor gene to express, which may then serve as the molecular identification of that cell. This process of differentiation or receptor gene regulation of olfactory sensory neurons has largely been enigmatic. Here, we showed that the important proto-oncogene in B lymphocyte terminal differentiation, B-Cell Leukemia/Lymphoma 6 (BCL-6), which codes for a sequence-specific transcription repressor, is expressed in olfactory sensory neurons in the mouse. We detected BCL-6 mRNA in most, if not all, mature olfactory sensory neurons by in situ hybridization histochemistry. Western blot analysis also revealed the presence of BCL-6 protein in the olfactory epithelium, but immunohistochemical analysis using anti-BCL-6 antibodies showed that only a subset of olfactory sensory neurons highly expressed BCL-6 protein. BCL-6 mRNA was detected as early as embryonic day 14 (E14) in most olfactory sensory neurons as in adults, and at E15, BCL-6 protein was detected in most cells that were likely to be differentiating into mature olfactory sensory neurons. Artificial induction of apoptosis of olfactory sensory neurons resulted in the decrease of BCL-6 mRNA, but during the subsequent phase of regeneration and differentiation, it markedly increased. Taken together, our results suggest the possibility that BCL-6 plays an important role in terminal differentiation not only in B lymphocytes but also in olfactory sensory neurons.


Tungstate-Induced Color-Pattern Modifications of Butterfly Wings are Independent of Stress Response and Ecdysteroid Effect

July 2005

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81 Reads

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34 Citations

ZOOLOGICAL SCIENCE

Systemic injections of sodium tungstate, a protein-tyrosine phosphatase (PTPase) inhibitor, to pupae immediately after pupation have been shown to efficiently produce characteristic color-pattern modifications on the wings of many species of butterflies. Here we demonstrated that the tungstate-induced modification pattern was entirely different from other chemically-induced ones in a species of nymphalid butterfly Junonia (Precis) orithya. In this species, the systemic injections of tungstate produced characteristic expansion of black area and shrinkage of white area together with the move of parafocal elements toward the wing base. Overall, pattern boundaries became obscure. In contrast, an entirely different modification pattern, overall darkening of wings, was observed by the injections of stress-inducing chemicals, thapsigargin, ionomycin, or geldanamycin, to pupae under the rearing conditions for the adult summer form. On the ventral wings, this darkening was due to an increase of the proportion of peppered dark scales, which was reminiscent of the natural fall form of this species. Under the same rearing conditions, the injections of ecdysteroid, which is a well-known hormone being responsible for the seasonal polyphenism of nymphalid butterflies, yielded overall expansion of orange area especially around eyespots. Taken together, we conclude that the tungstate-induced modifications are clearly distinguishable from those of stress response and ecdysteroid effect. This conclusion then suggests that the putative PTPase signaling pathway that is sensitive to tungstate uniquely contributes to the wing-wide color-pattern development in butterflies.


Availability of short amino acid sequences in proteins

April 2005

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33 Reads

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36 Citations

Protein Science

Much attention is being paid to protein databases as an important information source for proteome research. Although used extensively for similarity searches, protein databases themselves have not fully been characterized. In a systematic attempt to reveal protein-database characters that could contribute to revealing how protein chains are constructed, frequency distributions of all possible combinatorial sets of three, four, and five amino acids ("triplets," "quartets," and "pentats"; collectively called constituent sequences) have been examined in the nonredundant (nr) protein database, demonstrating the existence of nonrandom bias in their "availability" at the population level. Nonexistent short sequences of pentats were found that showed low availability in biological proteins against their expected probabilities of occurrence. Among them, six representative ones were successfully synthesized as peptides with reasonably high yields in a conventional Fmoc method, excluding the possibility that a putative physicochemical energy barrier in forming them could be a direct cause for the low availability. They were also expressed as soluble fusion proteins in a conventional Escherichia coli BL21Star(DE3) system with reasonably high yield, again excluding a possible difficulty in their biological synthesis. Together, these results suggest that information on three-dimensional structures and functions of proteins exists in the context of connections of short constituent sequences, and that proteins are composed of evolutionarily selected constituent sequences, which are reflected in their availability differences in the database. These results may have biological implications for protein structural studies.


Morphological Comparison of Pupal Wing Cuticle Patterns in Butterflies

February 2005

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29 Reads

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41 Citations

ZOOLOGICAL SCIENCE

Butterfly wing color-patterns are determined in the prospective wing tissues during the late larval and early pupal stages. To study the cellular differentiation process of wings, morphological knowledge on pupal wings is prerequisite. Here we systematically examined morphological patterns of the pupal wing cuticular surface in a wide variety of nymphalid butterflies in relation to adult color-patterns. Several kinds of pupal wing patterns corresponding to particular adult color-pattern elements were widely observed in many species. Especially noteworthy were the pupal "focal" spots corresponding to the adult border ocelli system, which were detected in many species of Nymphalinae, Apaturinae, Argynninae, Satyrinae, and Danainae. Striped patterns on the pupal wing cuticle seen in some species of Limenitinae, Ariadnae, and Marpesiinae directly corresponded to those of the adult wings. In Vanessa cardui, eyespot-like pattern elements were tentatively produced during development in the wing tissue underneath the pupal spots and subsequently erased, suggesting a mechanism for producing novel color-patterns in the course of development and evolution. The pupal focal spots reasonably correlated with the adult eyespots in size in Precis orithya and Ypthima argus. We physically damaged the pupal focal spots and their corresponding cells underneath in these species, which abolished or inhibited the formation of the adult eyespots. Taken together, our results clarified that pupal cuticle patterns were often indicative of the adult color-patterns and apparently reflect molecular activity of organizing centers for the adult color-pattern formation at least in nymphalid butterflies.


Color-pattern Modifications and Speciation in Butterflies of the Genus Vanessa and its Related Genera Cynthia and Bassaris

October 2004

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96 Reads

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23 Citations

ZOOLOGICAL SCIENCE

We have previously shown that the systemic injection of sodium tungstate, a protein-tyrosine phosphatase (PTPase) inhibitor, to pupae immediately after pupation efficiently produces characteristic color-pattern modifications on the wings of many species of butterflies including Vanessa indica and Cynthia cardui. In these species, the black spots reduced in size in response to the treatment. Similar modifications are occasionally seen in the field-caught aberrant individuals. Exceptionally, however, a C. cardui individual with enlarged black spots ("reversed" modification pattern) has been reported. Here we show that these modified patterns of V. indica and C. cardui are quite similar to the normal color-patterns of other Vanessa species. V. indica with tungstate-induced modifications resembled V. tameamea, V. samani, and Bassaris itea, whereas V. dilecta, V. atalanta, and V. dejeanii are similar to the "reversed" individual. Most features seen in the experimentally-modified V. indica were observed throughout the fore- and hindwings of V. samani. In contrast, the experimentally-induced color-patterns of C. cardui did not parallel variation of Cynthia butterflies. Since it has been proposed that a hypothetical transduction pathway with a PTPase for the scale-cell differentiation globally coordinates the wing-wide color-patterns, our findings suggest that spontaneous mutations in genes in this hypothetical pathway might have played a major role in creating new color-patterns and species in the Vanessa genus but not in the Cynthia genus. This evolutionary mechanism may probably be shared more widely in Lepidoptera, although this would not be a sole determinant for the color-pattern development and evolution.


Citations (13)


... Except for the general tools for genome annotation there are also classifiers which point to specific membrane protein families and its division into classes. For example to classify members of a GPCRs family several computational methods have been used, namely a phylogenetic analysis (an A-F GPCRs classification system [36]; with a Hidden Markov Models-based search (GRAFS [37] – see Fig. 1), self-organizing maps [38], neighbor-joining [39], unweighted pair group method with arithmetic mean [40], multidimensional scaling [41]. A useful hierarchical integration of various alignment-based and alignment-free classification methods was implemented in a 7TMRmine web server for discovering 7TMRs (seven transmembrane region-containing receptors) [42]. ...

Reference:

Modeling of Membrane Proteins
Alignment‐Free Classification of G‐Protein‐Coupled Receptors Using Self‐Organizing Maps.
  • Citing Article
  • August 2006

ChemInform

... The validity and significance of the inhibitory effects under nonoptimum conditions may be arguable, but the PIA results under nonoptimum conditions should be considered a first step in identifying functional sites, and thus in the development of novel drugs. Another support for PIA comes from a group of studies that stresses the important contribution of short constituent sequences (SCSs) of proteins to secondary structures and the functionality of proteins [42][43][44][45][46][47][48][49][50][51][52][53][54]. A well-known structural prediction approach, ROSETTA, is also based on data collection of SCSs from the PDB [55,56]. ...

Secondary Structure Characterization Based on Amino Acid Composition and Availability in Proteins
  • Citing Article
  • March 2010

Journal of Chemical Information and Modeling

... BCL6 has also been identified as a pro-neurogenic factor during embryonic neocortex development [77], playing roles in progenitor cell differentiation [78] as well as in the survival of cortical neurons [79] and olfactory sensory neurons [80]. The ablation of Ken impacted behavioral responses to visual stimuli in fruit-flies, including escape behavior and synaptic function in the giant fiber system [81], suggesting some potential conservation. ...

The Proto-oncogene BCL6 Promotes Survival of Olfactory Sensory Neurons
  • Citing Article
  • May 2010

Developmental Neurobiology

... These functions encompass axonal guidance and plasticity related to the previous exposure to odorants [83][84][85]. The presence of olfactory receptors in the autonomic nervous system ganglia supports the notion that they serve functions beyond odorant detection, including the response to molecules endogenously produced [86,87]. ...

Odorant Receptor Expression in the Mouse Cerebral Cortex
  • Citing Article
  • February 2004

Journal of Neurobiology

... For modified color patterns to be assimilated in a population, modifications should be functionally relevant. A gene responsible for a given plastic phenotype may be epistatically linked with different genes that have a survival advantage, as suggested in the case of Vanessa butterflies [38][39][40][41] and Zizeeria maha [43]. In the case of P. polytes, modifications can be readily functional if they are similar to the color patterns of unpalatable species. ...

Color-pattern Modifications and Speciation in Butterflies of the Genus Vanessa and its Related Genera Cynthia and Bassaris
  • Citing Article
  • October 2004

ZOOLOGICAL SCIENCE

... Ectopic color patterns and calcium signals are induced by puncture damage, not only in butterflies but also in fish [54], suggesting that butterfly and fish systems share a common mechanism of wound healing and color pattern development to some extent. Although the cellular and molecular mechanisms of color pattern development in butterfly wings have been studied intensively using several approaches, including comparative morphological approach [48,[55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71], surgical and physical approach [72][73][74][75][76], physiological approach [77][78][79][80], bioimaging approach [81][82][83][84][85][86], and genetic and molecular biological approach , the wound-healing process itself has not been studied at the cellular level in butterflies. ...

Morphological Comparison of Pupal Wing Cuticle Patterns in Butterflies
  • Citing Article
  • February 2005

ZOOLOGICAL SCIENCE

... The validity and significance of the inhibitory effects under nonoptimum conditions may be arguable, but the PIA results under nonoptimum conditions should be considered a first step in identifying functional sites, and thus in the development of novel drugs. Another support for PIA comes from a group of studies that stresses the important contribution of short constituent sequences (SCSs) of proteins to secondary structures and the functionality of proteins [42][43][44][45][46][47][48][49][50][51][52][53][54]. A well-known structural prediction approach, ROSETTA, is also based on data collection of SCSs from the PDB [55,56]. ...

Availability of short amino acid sequences in proteins
  • Citing Article
  • April 2005

Protein Science

... The butterfly pupal wing system mainly contains only two types of cells: epidermal (epithelial) cells that constitute the wing epidermis and free-moving hemocytes, and we differentially stained these two types of cells. We further showed that a general calcium inhibitor, ruthenium red, affected wing scale development, although the effect of thapsigargin, an inhibitor of Ca 2+ -ATPase (SERCA), on wing development in J. orithya has already been documented [52,108]. We then examined the effects of calcium inhibition by ruthenium red on damage repair and ectopic color patterns in the present study. ...

Tungstate-Induced Color-Pattern Modifications of Butterfly Wings are Independent of Stress Response and Ecdysteroid Effect
  • Citing Article
  • July 2005

ZOOLOGICAL SCIENCE

... In human brain and mouse brain, ITM2B has been found to be expressed in olfactory neurons, the cerebral cortex, hippocampus, and cerebellum. In the mouse, BCL6 expression is found in these regions as well [36][37][38][39][40]. In humans, although BCL6 is expressed in the brain [34], to our knowledge, its regional distribution has not been characterized. ...

The proto-oncogene BCL-6 is expressed in olfactory sensory neurons
  • Citing Article
  • November 2005

Neuroscience Research