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Guoping Feng - One of the best experts on this subject based on the ideXlab platform.

  • annual research review Transgenic Mouse models of childhood onset psychiatric disorders
    Journal of Child Psychology and Psychiatry, 2011
    Co-Authors: Holly R Robertson, Guoping Feng
    Abstract:

    Childhood-onset psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), mood disorders, obsessive compulsive spectrum disorders (OCSD), and schizophrenia (SZ), affect many school-age children, leading to a lower quality of life, including difficulties in school and personal relationships that persist into adulthood. Currently, the causes of these psychiatric disorders are poorly understood, resulting in difficulty diagnosing affected children, and insufficient treatment options. Family and twin studies implicate a genetic contribution for ADHD, ASD, mood disorders, OCSD, and SZ. Identification of candidate genes and chromosomal regions associated with a particular disorder provide targets for directed research, and understanding how these genes influence the disease state will provide valuable insights for improving the diagnosis and treatment of children with psychiatric disorders. Transgenic Mouse models are one important approach in the study of human diseases, allowing for the use of a variety of experimental approaches to dissect the contribution of a specific chromosomal or genetic abnormality in human disorders. While it is impossible to model an entire psychiatric disorder in a single Mouse model, these models can be extremely valuable in dissecting out the specific role of a gene, pathway, neuron subtype, or brain region in a particular abnormal behavior. In this review we discuss existing Transgenic Mouse models for childhood-onset psychiatric disorders. We compare the strength and weakness of various Transgenic Mouse models proposed for each of the common childhood-onset psychiatric disorders, and discuss future directions for the study of these disorders using cutting-edge genetic tools.

  • Transgenic Mouse models of childhood onset psychiatric disorders
    Journal of Child Psychology and Psychiatry, 2011
    Co-Authors: Holly R Robertson, Guoping Feng
    Abstract:

    Childhood onset psychiatric disorders including Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), Mood Disorders, Obsessive Compulsive Spectrum Disorders (OCSD), and Schizophrenia (SZ) affect many school age children. These children typically have a lower quality of life, including difficulties in school and personal relationships, and these problems persist into adulthood. Additionally, the treatment and support of these individuals causes severe financial and social burdens on society. Currently, the causes of these psychiatric disorders are poorly understood. This lack of knowledge results in difficulty diagnosing affected children, and insufficient treatment options. Family and twin linkage studies implicate a genetic contribution for ADHD, ASD, Mood Disorders, OCSD, and SZ (Hudziak and Faraone, 2010). In some cases single, rare genetic mutations lead to childhood onset psychiatric disorders (Hudziak and Faraone, 2010). Additionally, there is a hypothesis that other cases are multigenic, with many genes contributing small effects leading to the overall disease state (Hudziak and Faraone, 2010). Developmental and environmental factors can also influence the severity of symptoms observed in affected individuals leading to a “spectrum” of behaviors (Dick et al., 2010). Identification of candidate genes and chromosomal regions associated with a particular disorder provide targets for directed research, and understanding how these genes influence the disease state will provide valuable information for improving the diagnosis and treatment of children with psychiatric disorders. Animal models are one method commonly utilized in the study of human diseases. Specifically, animal models can overcome many of the confounding factors that limit research in human patients including genetic variability and environmental diversity. Some benefits of using Transgenic mice to model human diseases include genetically homogeneous populations, greater control over environmental conditions, shorter time between generations, pharmacological studies, and the opportunity for genetic manipulations. The generation of Transgenic Mouse models can therefore allow for a controlled approach in evaluating the consequences of a specific chromosomal or genetic abnormality observed in human patients. There are however limitations to using animal models to study psychiatric disorders. Most importantly, there are many behaviors of psychiatric disorders that are currently impossible to evaluate in a Mouse model. For example, obsessive thinking in OCD, and hallucinations in SZ cannot be assessed in mice. Thus, researchers are limited to modeling behaviors of psychiatric disorders that can be assessed in a Mouse including hyperactivity, social interactions, anxiety, and some types of learning and memory (Crawley, 2007). However, it is important to note that even behaviors that can be assessed in a Mouse are not an exact replica of human behavior. At best, we can make correlations between the observed Mouse behavior and known human behaviors in these disorders. It is also impossible to model an entire psychiatric disorder in a single animal model. Psychiatric disorders are complex disorders, and current technology cannot expect to encompass the entirety of such a complex disorder within a single model (Laporte et al., 2008). A more realistic approach is to model a specific behavior, or single genetic mutation associated with a disorder in an individual model. These models can then be used to dissect out the specific role of a gene, pathway, neuron subtype, or brain region in a particular behavior. Establishing a Transgenic Mouse as a model of a psychiatric disorder requires face, construct, and predictive validity. Face validity refers to the resemblance of the Mouse model phenotype to the symptoms of the human disorder. In some cases, rodent behaviors can be directly correlated to human symptoms. For example, pre-pulse inhibition (PPI), a test of sensory-motor gating, can be evaluated in both humans and rodents (Geyer, 2008). Other behaviors in mice are correlative to human behaviors. For example, tests to show anxiety-like behaviors in a Mouse include time spent in the open section of the elevated plus maze and emergence to light in the light dark emergence test. These particular behaviors are not observed in humans with anxiety; however the observation of the behavior in the Mouse is sufficient to draw a positive correlation in some cases. Table 1 lists behavior tests commonly used in characterizing Mouse models of psychiatric disorders. Table 1 Table of common behavior tests used to characterize animal models of childhood onset psychiatric disorders. Construct validity refers to similarities in the Mouse model to the underlying cause of the human disorder. Gene association and linkage studies can implicate certain genes which are then targeted in Transgenic Mouse models and therefore partially address construct validity. Finally, predictive validity refers to the expected response in the Mouse model to treatments as observed in human patients. Establishing predictive validity is helpful for evaluating the potential of future novel therapies for a particular disorder. In this review we will discuss Transgenic Mouse models for childhood onset psychiatric disorders. We will introduce the currently proposed Transgenic animal models for common childhood onset psychiatric disorders, and discuss future directions for the study of these disorders using cutting-edge genetic tools. We apologize that due to page limitations, we were unable to list all relevant references in this review.

Junichi Miyazaki - One of the best experts on this subject based on the ideXlab platform.

  • a Transgenic Mouse line that retains cre recombinase activity in mature oocytes irrespective of thecretransgene transmission
    Biochemical and Biophysical Research Communications, 1997
    Co-Authors: Katsunaga Sakai, Junichi Miyazaki
    Abstract:

    The Cre/loxP site-specific recombination system derived from bacteriophage P1 provides a convenient tool for directed modifications of genomes in various organisms. To exploit Cre-mediated manipulation of Mouse genomic sequences at the zygote stage, we have developed a Transgenic Mouse line carrying the CAG-cre transgene in which the cre gene is under control of the cytomegalovirus immediate early enhancer-chicken beta-actin hybrid (CAG) promoter. The activity of the Cre recombinase at early stages of development was examined by crossing the CAG-cre Transgenic mice to another Transgenic Mouse line carrying a reporter gene construct, CAG-CAT-Z, which directs expression of the E. coli lacZ gene upon Cre-mediated excision of the loxP-flanked chloramphenicol acetyltransferase (CAT) gene located between the CAG promoter and the lacZ gene. PCR-based analysis of F1 progeny from CAG-cre males x CAG-CAT-Z females showed that transmission of the CAG-cre transgene was accompanied by the complete deletion of the CAT gene of the CAG-CAT-Z transgene in all tissues, and that this deletion was never observed in the progeny without transmission of the CAG-cre gene. On the other hand, analysis of F1 mice from CAG-CAT-Z males x CAG-cre females showed that the CAG-CAT-Z transgene had undergone complete deletion of the CAT gene in all tissues irrespective of the cotransmission of the CAG-cre gene. This Cre-mediated recombination in F1 mice occurred before the two-cell stage of embryonic development, as shown by X-gal staining. The results suggest that the CAG-cre transgene is expressed in developing oocytes of CAG-cre Transgenic mice, and Cre mRNA and/or protein are retained in mature oocytes irrespective of the transmission of the CAG-cre transgene, resulting in efficient Cre-mediated recombination of paternally derived target genes upon fertilization. The CAG-cre Transgenic Mouse should serve as a useful tool to introduce prescribed genetic modifications into the Mouse embryo at the zygote stage.

  • a Transgenic Mouse line that retains cre recombinase activity in mature oocytes irrespective of the cre transgene transmission
    Biochemical and Biophysical Research Communications, 1997
    Co-Authors: Katsunaga Sakai, Junichi Miyazaki
    Abstract:

    The Cre/loxP site-specific recombination system derived from bacteriophage P1 provides a convenient tool for directed modifications of genomes in various organisms. To exploit Cre-mediated manipulation of Mouse genomic sequences at the zygote stage, we have developed a Transgenic Mouse line carrying the CAG-cre transgene in which the cre gene is under control of the cytomegalovirus immediate early enhancer-chicken beta-actin hybrid (CAG) promoter. The activity of the Cre recombinase at early stages of development was examined by crossing the CAG-cre Transgenic mice to another Transgenic Mouse line carrying a reporter gene construct, CAG-CAT-Z, which directs expression of the E. coli lacZ gene upon Cre-mediated excision of the loxP-flanked chloramphenicol acetyltransferase (CAT) gene located between the CAG promoter and the lacZ gene. PCR-based analysis of F1 progeny from CAG-cre males x CAG-CAT-Z females showed that transmission of the CAG-cre transgene was accompanied by the complete deletion of the CAT gene of the CAG-CAT-Z transgene in all tissues, and that this deletion was never observed in the progeny without transmission of the CAG-cre gene. On the other hand, analysis of F1 mice from CAG-CAT-Z males x CAG-cre females showed that the CAG-CAT-Z transgene had undergone complete deletion of the CAT gene in all tissues irrespective of the cotransmission of the CAG-cre gene. This Cre-mediated recombination in F1 mice occurred before the two-cell stage of embryonic development, as shown by X-gal staining. The results suggest that the CAG-cre transgene is expressed in developing oocytes of CAG-cre Transgenic mice, and Cre mRNA and/or protein are retained in mature oocytes irrespective of the transmission of the CAG-cre transgene, resulting in efficient Cre-mediated recombination of paternally derived target genes upon fertilization. The CAG-cre Transgenic Mouse should serve as a useful tool to introduce prescribed genetic modifications into the Mouse embryo at the zygote stage.

  • islet amyloid polypeptide amylin in pancreatic β cell line derived from Transgenic Mouse insulinoma
    Diabetes, 1992
    Co-Authors: Azuma Kanatsuka, Kenichi Yamamura, Junichi Miyazaki, Hideichi Makino, Takahide Yamaguchi, Haruhiko Ohsawa, Yoshiharu Tokuyama, Takeo Saitoh, Sho Yoshida
    Abstract:

    We examined the production and secretion of IAPP in a β-cell line, MIN6, which is derived from an insulinoma obtained by targeted expression of the SV40 T-antigen gene in a Transgenic Mouse. RNA blot analysis revealed an abundance of IAPP and insulin II mRNA in the cells, findings comparable with those in the pancreas of a normal Mouse. The presence of IAPP and insulin was confirmed immunohistochemically and by RIA. Analysis of the reverse-phase HPLC identified IAPP in cells with authentic Mouse IAPP. Raising the glucose concentration from 5.6 to 25 mM failed to induce increments in IAPP and insulin II mRNAs. The cells secrete IAPP and insulin for short- and long-term incubations in response to concentration of glucose in the medium. These features resemble those of islet cells from normal animals. This β-cell line will aid in analyzing the regulation of IAPP gene expression and the mechanisms of IAPP biosynthesis and secretion.

John J Mccarthy - One of the best experts on this subject based on the ideXlab platform.

  • a novel tetracycline responsive Transgenic Mouse strain for skeletal muscle specific gene expression
    Skeletal Muscle, 2018
    Co-Authors: Charlotte A Peterson, Masahiro Iwata, Davis A Englund, Yuan Wen, Cory M Dungan, Kevin A Murach, Ivan J Vechetti, Christopher B Mobley, John J Mccarthy
    Abstract:

    The tetracycline-responsive system (Tet-ON/OFF) has proven to be a valuable tool for manipulating gene expression in an inducible, temporal, and tissue-specific manner. The purpose of this study was to create and characterize a new Transgenic Mouse strain utilizing the human skeletal muscle α-actin (HSA) promoter to drive skeletal muscle-specific expression of the reverse tetracycline transactivator (rtTA) gene which we have designated as the HSA-rtTA Mouse. To confirm the HSA-rtTA Mouse was capable of driving skeletal muscle-specific expression, we crossed the HSA-rtTA Mouse with the tetracycline-responsive histone H2B-green fluorescent protein (H2B-GFP) Transgenic Mouse in order to label myonuclei. Reverse transcription-PCR confirmed skeletal muscle-specific expression of rtTA mRNA, while single-fiber analysis showed highly effective GFP labeling of myonuclei in both fast- and slow-twitch skeletal muscles. Pax7 immunohistochemistry of skeletal muscle cross-sections revealed no appreciable GFP expression in satellite cells. The HSA-rtTA Transgenic Mouse allows for robust, specific, and inducible gene expression across muscles of different fiber types. The HSA-rtTA Mouse provides a powerful tool to manipulate gene expression in skeletal muscle.

  • inducible cre Transgenic Mouse strain for skeletal muscle specific gene targeting
    Skeletal Muscle, 2012
    Co-Authors: John J Mccarthy, Ratchakrit Srikuea, Tyler J Kirby, Charlotte A Peterson, Karyn A Esser
    Abstract:

    The use of the Cre/loxP system for gene targeting has been proven to be a powerful tool for understanding gene function. The purpose of this study was to create and characterize an inducible, skeletal muscle-specific Cre Transgenic Mouse strain. To achieve skeletal muscle-specific expression, the human α-skeletal actin promoter was used to drive expression of a chimeric Cre recombinase containing two mutated estrogen receptor ligand-binding domains. Western blot analysis, PCR and β-galactosidase staining confirmed that Cre-mediated recombination was restricted to limb and craniofacial skeletal muscles only after tamoxifen administration. A Transgenic Mouse was created that allows inducible, gene targeting of floxed genes in adult skeletal muscle of different developmental origins. This new Mouse will be of great utility to the skeletal muscle community.

Holly R Robertson - One of the best experts on this subject based on the ideXlab platform.

  • annual research review Transgenic Mouse models of childhood onset psychiatric disorders
    Journal of Child Psychology and Psychiatry, 2011
    Co-Authors: Holly R Robertson, Guoping Feng
    Abstract:

    Childhood-onset psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), mood disorders, obsessive compulsive spectrum disorders (OCSD), and schizophrenia (SZ), affect many school-age children, leading to a lower quality of life, including difficulties in school and personal relationships that persist into adulthood. Currently, the causes of these psychiatric disorders are poorly understood, resulting in difficulty diagnosing affected children, and insufficient treatment options. Family and twin studies implicate a genetic contribution for ADHD, ASD, mood disorders, OCSD, and SZ. Identification of candidate genes and chromosomal regions associated with a particular disorder provide targets for directed research, and understanding how these genes influence the disease state will provide valuable insights for improving the diagnosis and treatment of children with psychiatric disorders. Transgenic Mouse models are one important approach in the study of human diseases, allowing for the use of a variety of experimental approaches to dissect the contribution of a specific chromosomal or genetic abnormality in human disorders. While it is impossible to model an entire psychiatric disorder in a single Mouse model, these models can be extremely valuable in dissecting out the specific role of a gene, pathway, neuron subtype, or brain region in a particular abnormal behavior. In this review we discuss existing Transgenic Mouse models for childhood-onset psychiatric disorders. We compare the strength and weakness of various Transgenic Mouse models proposed for each of the common childhood-onset psychiatric disorders, and discuss future directions for the study of these disorders using cutting-edge genetic tools.

  • Transgenic Mouse models of childhood onset psychiatric disorders
    Journal of Child Psychology and Psychiatry, 2011
    Co-Authors: Holly R Robertson, Guoping Feng
    Abstract:

    Childhood onset psychiatric disorders including Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), Mood Disorders, Obsessive Compulsive Spectrum Disorders (OCSD), and Schizophrenia (SZ) affect many school age children. These children typically have a lower quality of life, including difficulties in school and personal relationships, and these problems persist into adulthood. Additionally, the treatment and support of these individuals causes severe financial and social burdens on society. Currently, the causes of these psychiatric disorders are poorly understood. This lack of knowledge results in difficulty diagnosing affected children, and insufficient treatment options. Family and twin linkage studies implicate a genetic contribution for ADHD, ASD, Mood Disorders, OCSD, and SZ (Hudziak and Faraone, 2010). In some cases single, rare genetic mutations lead to childhood onset psychiatric disorders (Hudziak and Faraone, 2010). Additionally, there is a hypothesis that other cases are multigenic, with many genes contributing small effects leading to the overall disease state (Hudziak and Faraone, 2010). Developmental and environmental factors can also influence the severity of symptoms observed in affected individuals leading to a “spectrum” of behaviors (Dick et al., 2010). Identification of candidate genes and chromosomal regions associated with a particular disorder provide targets for directed research, and understanding how these genes influence the disease state will provide valuable information for improving the diagnosis and treatment of children with psychiatric disorders. Animal models are one method commonly utilized in the study of human diseases. Specifically, animal models can overcome many of the confounding factors that limit research in human patients including genetic variability and environmental diversity. Some benefits of using Transgenic mice to model human diseases include genetically homogeneous populations, greater control over environmental conditions, shorter time between generations, pharmacological studies, and the opportunity for genetic manipulations. The generation of Transgenic Mouse models can therefore allow for a controlled approach in evaluating the consequences of a specific chromosomal or genetic abnormality observed in human patients. There are however limitations to using animal models to study psychiatric disorders. Most importantly, there are many behaviors of psychiatric disorders that are currently impossible to evaluate in a Mouse model. For example, obsessive thinking in OCD, and hallucinations in SZ cannot be assessed in mice. Thus, researchers are limited to modeling behaviors of psychiatric disorders that can be assessed in a Mouse including hyperactivity, social interactions, anxiety, and some types of learning and memory (Crawley, 2007). However, it is important to note that even behaviors that can be assessed in a Mouse are not an exact replica of human behavior. At best, we can make correlations between the observed Mouse behavior and known human behaviors in these disorders. It is also impossible to model an entire psychiatric disorder in a single animal model. Psychiatric disorders are complex disorders, and current technology cannot expect to encompass the entirety of such a complex disorder within a single model (Laporte et al., 2008). A more realistic approach is to model a specific behavior, or single genetic mutation associated with a disorder in an individual model. These models can then be used to dissect out the specific role of a gene, pathway, neuron subtype, or brain region in a particular behavior. Establishing a Transgenic Mouse as a model of a psychiatric disorder requires face, construct, and predictive validity. Face validity refers to the resemblance of the Mouse model phenotype to the symptoms of the human disorder. In some cases, rodent behaviors can be directly correlated to human symptoms. For example, pre-pulse inhibition (PPI), a test of sensory-motor gating, can be evaluated in both humans and rodents (Geyer, 2008). Other behaviors in mice are correlative to human behaviors. For example, tests to show anxiety-like behaviors in a Mouse include time spent in the open section of the elevated plus maze and emergence to light in the light dark emergence test. These particular behaviors are not observed in humans with anxiety; however the observation of the behavior in the Mouse is sufficient to draw a positive correlation in some cases. Table 1 lists behavior tests commonly used in characterizing Mouse models of psychiatric disorders. Table 1 Table of common behavior tests used to characterize animal models of childhood onset psychiatric disorders. Construct validity refers to similarities in the Mouse model to the underlying cause of the human disorder. Gene association and linkage studies can implicate certain genes which are then targeted in Transgenic Mouse models and therefore partially address construct validity. Finally, predictive validity refers to the expected response in the Mouse model to treatments as observed in human patients. Establishing predictive validity is helpful for evaluating the potential of future novel therapies for a particular disorder. In this review we will discuss Transgenic Mouse models for childhood onset psychiatric disorders. We will introduce the currently proposed Transgenic animal models for common childhood onset psychiatric disorders, and discuss future directions for the study of these disorders using cutting-edge genetic tools. We apologize that due to page limitations, we were unable to list all relevant references in this review.

Masahiro Iwata - One of the best experts on this subject based on the ideXlab platform.

  • a novel tetracycline responsive Transgenic Mouse strain for skeletal muscle specific gene expression
    Skeletal Muscle, 2018
    Co-Authors: Charlotte A Peterson, Masahiro Iwata, Davis A Englund, Yuan Wen, Cory M Dungan, Kevin A Murach, Ivan J Vechetti, Christopher B Mobley, John J Mccarthy
    Abstract:

    The tetracycline-responsive system (Tet-ON/OFF) has proven to be a valuable tool for manipulating gene expression in an inducible, temporal, and tissue-specific manner. The purpose of this study was to create and characterize a new Transgenic Mouse strain utilizing the human skeletal muscle α-actin (HSA) promoter to drive skeletal muscle-specific expression of the reverse tetracycline transactivator (rtTA) gene which we have designated as the HSA-rtTA Mouse. To confirm the HSA-rtTA Mouse was capable of driving skeletal muscle-specific expression, we crossed the HSA-rtTA Mouse with the tetracycline-responsive histone H2B-green fluorescent protein (H2B-GFP) Transgenic Mouse in order to label myonuclei. Reverse transcription-PCR confirmed skeletal muscle-specific expression of rtTA mRNA, while single-fiber analysis showed highly effective GFP labeling of myonuclei in both fast- and slow-twitch skeletal muscles. Pax7 immunohistochemistry of skeletal muscle cross-sections revealed no appreciable GFP expression in satellite cells. The HSA-rtTA Transgenic Mouse allows for robust, specific, and inducible gene expression across muscles of different fiber types. The HSA-rtTA Mouse provides a powerful tool to manipulate gene expression in skeletal muscle.