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Dive into the research topics where Mahendra Wagle is active.

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Featured researches published by Mahendra Wagle.


The Journal of Neuroscience | 2009

Ethanol-Modulated Camouflage Response Screen in Zebrafish Uncovers a Novel Role for cAMP and Extracellular Signal-Regulated Kinase Signaling in Behavioral Sensitivity to Ethanol

Jisong Peng; Mahendra Wagle; Thomas Mueller; Priya Mathur; Brent L. Lockwood; Sandrine Bretaud; Su Guo

Ethanol, a widely abused substance, elicits evolutionarily conserved behavioral responses in a concentration-dependent manner in vivo. The molecular mechanisms underlying such behavioral sensitivity to ethanol are poorly understood. While locomotor-based behavioral genetic screening is successful in identifying genes in invertebrate models, such complex behavior-based screening has proven difficult for recovering genes in vertebrates. Here we report a novel and tractable ethanol response in zebrafish. Using this ethanol-modulated camouflage response as a screening assay, we have identified a zebrafish mutant named fantasma (fan), which displays reduced behavioral sensitivity to ethanol. Positional cloning reveals that fan encodes type 5 adenylyl cyclase (AC5). fan/ac5 is required to maintain the phosphorylation of extracellular signal-regulated kinase (ERK) in the forebrain structures, including the telencephalon and hypothalamus. Partial inhibition of phosphorylation of ERK in wild-type zebrafish mimics the reduction in sensitivity to stimulatory effects of ethanol observed in the fan mutant, whereas, strikingly, strong inhibition of phosphorylation of ERK renders a stimulatory dose of ethanol sedating. Since previous studies in Drosophila and mice show a role of cAMP signaling in suppressing behavioral sensitivity to ethanol, our findings reveal a novel, isoform-specific role of AC signaling in promoting ethanol sensitivity, and suggest that the phosphorylation level of the downstream effector ERK is a critical “gatekeeper” of behavioral sensitivity to ethanol.


Developmental Neurobiology | 2012

Toward molecular genetic dissection of neural circuits for emotional and motivational behaviors.

Su Guo; Mahendra Wagle; Priya Mathur

How does the brain process the emotional meaning of sensory stimuli and in turn drive behavior? Studies in the mammalian systems have identified various brain regions and neurotransmitter systems that are critical for emotional and motivational behaviors and have implicated their involvement in neuropsychiatric disorders including anxiety, depression, schizophrenia, and addiction. Despite these significant advancements, the precise neural circuitry underlying emotional and motivational behaviors remains to be understood at molecular and cellular levels. In this review, we discuss how the vertebrate model organism zebrafish can help us gain insights into the underlying circuitry. We first describe studies of several simple and relevant preference behaviors in this model organism, and then discuss approaches and technologies that can be used to uncover the development and function of neural circuits underlying these behaviors.


The Journal of Neuroscience | 2011

Corticotropin-Releasing Factor Critical for Zebrafish Camouflage Behavior Is Regulated by Light and Sensitive to Ethanol

Mahendra Wagle; Priya Mathur; Su Guo

The zebrafish camouflage response is an innate “hard-wired” behavior that offers an excellent opportunity to explore neural circuit assembly and function. Moreover, the camouflage response is sensitive to ethanol, making it a tractable system for understanding how ethanol influences neural circuit development and function. Here we report the identification of corticotropin-releasing factor (CRF) as a critical component of the camouflage response pathway. We further show that ethanol, having no direct effect on the visual sensory system or the melanocytes, acts downstream of retinal ganglion cells and requires the CRF-proopiomelanocortin pathway to exert its effect on camouflage. Treatment with ethanol, as well as alteration of light exposure that changes sensory input into the camouflage circuit, robustly modifies CRF expression in subsets of neurons. Activity of both adenylyl cyclase 5 and extracellular signal-regulated kinase (ERK) is required for such ethanol-induced or light-induced plasticity of crf expression. These results reveal an essential role of a peptidergic pathway in camouflage that is regulated by light and influenced by ethanol at concentrations relevant to abuse and anxiolysis, in a cAMP-dependent and ERK-dependent manner. We conclude that this ethanol-modulated camouflage response represents a novel and relevant system for molecular genetic dissection of a neural circuit that is regulated by light and sensitive to ethanol.


The Journal of Neuroscience | 2014

Heterogeneously Expressed fezf2 Patterns Gradient Notch Activity in Balancing the Quiescence, Proliferation, and Differentiation of Adult Neural Stem Cells

Michael A. Berberoglu; Zhiqiang Dong; Guangnan Li; Jiashun Zheng; Luz del Carmen G. Trejo Martinez; Jisong Peng; Mahendra Wagle; Brian Reichholf; Claudia Petritsch; Hao Li; Samuel J. Pleasure; Su Guo

Balancing quiescence, self-renewal, and differentiation in adult stem cells is critical for tissue homeostasis. The underlying mechanisms, however, remain incompletely understood. Here we identify Fezf2 as a novel regulator of fate balance in adult zebrafish dorsal telencephalic neural stem cells (NSCs). Transgenic reporters show intermingled fezf2-GFPhi quiescent and fezf2-GFPlo proliferative NSCs. Constitutive or conditional impairment of fezf2 activity demonstrates its requirement for maintaining quiescence. Analyses of genetic chimeras reveal a dose-dependent role of fezf2 in NSC activation, suggesting that the difference in fezf2 levels directionally biases fate. Single NSC profiling coupled with genetic analysis further uncovers a fezf2-dependent gradient Notch activity that is high in quiescent and low in proliferative NSCs. Finally, fezf2-GFPhi quiescent and fezf2-GFPlo proliferative NSCs are observed in postnatal mouse hippocampus, suggesting possible evolutionary conservation. Our results support a model in which fezf2 heterogeneity patterns gradient Notch activity among neighbors that is critical to balance NSC fate.


Journal of Visualized Experiments | 2011

Time-lapse Live Imaging of Clonally Related Neural Progenitor Cells in the Developing Zebrafish Forebrain

Zhiqiang Dong; Mahendra Wagle; Su Guo

Precise patterns of division, migration and differentiation of neural progenitor cells are crucial for proper brain development and function. To understand the behavior of neural progenitor cells in the complex in vivo environment, time-lapse live imaging of neural progenitor cells in an intact brain is critically required. In this video, we exploit the unique features of zebrafish embryos to visualize the development of forebrain neural progenitor cells in vivo. We use electroporation to genetically and sparsely label individual neural progenitor cells. Briefly, DNA constructs coding for fluorescent markers were injected into the forebrain ventricle of 22 hours post fertilization (hpf) zebrafish embryos and electric pulses were delivered immediately. Six hours later, the electroporated zebrafish embryos were mounted with low melting point agarose in glass bottom culture dishes. Fluorescently labeled neural progenitor cells were then imaged for 36 hours with fixed intervals under a confocal microscope using water dipping objective lens. The present method provides a way to gain insights into the in vivo development of forebrain neural progenitor cells and can be applied to other parts of the central nervous system of the zebrafish embryo.


Communicative & Integrative Biology | 2009

Camouflage response in zebrafish: A model for genetic dissection of molecular and cellular circuitries underlying alcoholism

Su Guo; Jisong Peng; Mahendra Wagle; Thomas Müller; Priya Mathur

Ethanol is a widely abused drug. Sensitivity to its acute effects has been strongly correlated with the risk of developing alcoholism in humans. Despite the importance of genetics in human alcoholism and alcohol-related diseases, the identification of genes has been difficult due to the complex nature of these disorders. We recently demonstrate that genetic screening using a simple and tractable ethanol-sensitive camouflage response in zebrafish can efficiently uncover genes that alter ethanol-modulated behaviors similarly observable in mammals. We isolated the fantasma (fan) mutant, and showed that it not only disrupts ethanol-modulated camouflage response, but also impairs behavioral sensitivity to ethanol. fan encodes the evolutionarily conserved adenylyl cyclase 5 (AC5) that regulates the phosphorylation of extracellular-signal-regulated-kinase (ERK) in the brain. Pharmacological perturbation of the phosphorylation of ERK uncovered that it is a critical “gatekeeper” of behavioral sensitivity to ethanol. Therefore, ethanol-modulated camouflage response screen is a powerful system for molecular genetic dissection of neural circuits that are sensitive to ethanol. We propose that polymorphisms in ac5 or genes of the ERK signaling pathway may contribute to susceptibility of alcoholism and alcohol-related medical disorders in humans.


Journal of Neurogenetics | 2017

Heritable natural variation of an anxiety-like behavior in larval zebrafish

Mahendra Wagle; Juliana Nguyen; Shinwoo Lee; Noah Zaitlen; Su Guo

Abstract Complex behaviors are often observed at a spectrum in the population, and psychiatric disorders represent extremes of such behavioral spectra. While grasping the underlying cellular and molecular basis of these disorders represents a major challenge, it is believed that studies of complex behaviors in model organisms, where genotyping and phenotyping can be more conveniently carried out and cause–effect relationships can be further discerned, will help address this challenge. Here we report the characterization of a natural dark aversion behavior in larval zebrafish, which is previously shown to be fear or anxiety-associated. Phenotyping ∼200 individuals using a light/dark choice assay uncovered that, while a majority of individuals displayed medium level of dark aversion (mda), a small number of individuals exhibited strong dark aversion (sda), and a third small cohort showed variable dark aversion (vda). Through selective breeding and phenotyping of the next generation, we demonstrated that both the sda and vda traits are heritable, with sda being invariable while vda being highly variable across multiple trials. Additionally, sda appears to be recessive and vda appears to be dominant over the common allele(s) in the population. Moreover, compared to vda, sda showed increased thigmotaxis (preference for the walls in an open field), another measure of anxiety. Together, these findings reveal a naturally heritable variation of anxiety-like behavior in a tractable model organism, thereby laying foundation for future dissection of the underlying molecular and cellular mechanisms.


Methods of Molecular Biology | 2017

Antibody Uptake Assay in the Embryonic Zebrafish Forebrain to Study Notch Signaling Dynamics in Neural Progenitor Cells In Vivo

Kai Tong; Mahendra Wagle; Su Guo

Stem cells can generate cell fate heterogeneity through asymmetric cell division (ACD). ACD derives from the asymmetric segregation of fate-determining molecules and/or organelles in the dividing cell. Radial glia in the embryonic zebrafish forebrain are an excellent model for studying the molecular mechanisms regulating ACD of stem cells in vertebrates, especially for live imaging concerning in vivo molecular and cellular dynamics. Due to the current difficulty in expressing fluorescent reporter-tagged proteins at physiological levels in zebrafish for live imaging, we have developed an antibody uptake assay to label proteins in live embryonic zebrafish forebrain with high specificity. DeltaD is a transmembrane ligand in Notch signaling pathway in the context of ACD of radial glia in zebrafish. By using this assay, we have successfully observed the in vivo dynamics of DeltaD for studying ACD of radial glia in the embryonic zebrafish forebrain.


Frontiers in Molecular Neuroscience | 2017

MicroRNA-133b Negatively Regulates Zebrafish Single Mauthner-Cell Axon Regeneration through Targeting tppp3 in Vivo

Rongchen Huang; Min Chen; Leiqing Yang; Mahendra Wagle; Su Guo; Bing Hu

Axon regeneration, fundamental to nerve repair, and functional recovery, relies on rapid changes in gene expression attributable to microRNA (miRNA) regulation. MiR-133b has been proved to play an important role in different organ regeneration in zebrafish, but its role in regulating axon regeneration in vivo is still controversial. Here, combining single-cell electroporation with a vector-based miRNA-expression system, we have modulated the expression of miR-133b in Mauthner-cells (M-cells) at the single-cell level in zebrafish. Through in vivo imaging, we show that overexpression of miR-133b inhibits axon regeneration, whereas down-regulation of miR-133b, promotes axon outgrowth. We further show that miR-133b regulates axon regeneration by directly targeting a novel regeneration-associated gene, tppp3, which belongs to Tubulin polymerization-promoting protein family. Gain or loss-of-function of tppp3 experiments indicated that tppp3 was a novel gene that could promote axon regeneration. In addition, we observed a reduction of mitochondrial motility, which have been identified to have a positive correlation with axon regeneration, in miR-133b overexpressed M-cells. Taken together, our work provides a novel way to study the role of miRNAs in individual cell and establishes a critical cell autonomous role of miR-133b in zebrafish M-cell axon regeneration. We propose that up-regulation of the newly founded regeneration-associated gene tppp3 may enhance axonal regeneration.


International Journal of Developmental Neuroscience | 2012

Understanding neurotransmitter-neuropeptide regulation through neural circuits controlling innate behaviour

Mahendra Wagle; Su Guo

hereditary fatal childhood leukodystrophy, caused by mutation in aspartoacylase (ASPA) gene. In normal brain ASPA gene expression occurs in oligodendrocytes (OLs) and its first expression coincides with appearance of OL progenitors at embryonic stage E12.5 in the forebrain. A sign of hypomyelination, which correlates with pathophysiology of CD in young children, is detected in ASPA KO mouse brain during peak of myelination. In these mutant brains a continued proliferation of immature OLs, presence of highly acetylated histones H3 associated with epigenetic regulation of cell proliferation is observed. The process of myelin synthesis and myelination normally proceeds with repression of proliferation and initiation of differentiation/maturation of OLs. In order to understand developmental changes in gene expression and involvement of biological mechanisms in devastating demyelinating disease, we performed gene array analysis, microRNA and Metabolomics studies of normal and ASPA KO mouse cortical white matter (WM) tissue at P20, at the peak of myelination. Many studies have revealed the involvement of a set of required genes that play critical role in the process of normal OL maturation and myelination. However, alteration in regulatory mechanisms involving WM disorders is not understood at this time. We have identified a set of 331 negative and one of144 positive, differentially expressed genes between KO vs. wt WM. The gene ontology report shows down-regulation of a number of key genes belonging to the myelin family, as well as embryonic and postnatal developmental genes, which we are currently validating. Most significant observation includes increased oxidative stress during early developmental stages. Among several relevant molecular pathways, a cluster of histone genes are identified that are involved in nucleosome assembly or disassembly, modification of histones with indicated epigenetic role in the leukodystrophy.

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Su Guo

University of California

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Priya Mathur

University of California

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Jisong Peng

University of California

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Zhiqiang Dong

University of California

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Guangnan Li

University of California

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Hao Li

University of California

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Harrison Liu

University of California

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