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Yi-ping Hsueh - One of the best experts on this subject based on the ideXlab platform.
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Haploinsufficiency of autism causative gene TBR1 impairs olfactory discrimination and neuronal activation of the olfactory system in mice
Molecular Autism, 2019Co-Authors: Tzyy-nan Huang, Tzu-li Yen, Lily R. Qiu, Hsiu-chun Chuang, Jason P. Lerch, Yi-ping HsuehAbstract:Background Autism spectrum disorders (ASD) exhibit two clusters of core symptoms, i.e., social and communication impairment, and repetitive behaviors and sensory abnormalities. Our previous study demonstrated that TBR1, a causative gene of ASD, controls axonal projection and neuronal activation of amygdala and regulates social interaction and vocal communication in a mouse model. Behavioral defects caused by TBR1 haploinsufficiency can be ameliorated by increasing neural activity via D-cycloserine treatment, an N-methyl-D-aspartate receptor (NMDAR) coagonist. In this report, we investigate the role of TBR1 in regulating olfaction and test whether D-cycloserine can also improve olfactory defects in TBR1 mutant mice. Methods We used TBR1 ^ +/− mice as a model to investigate the function of TBR1 in olfactory sensation and discrimination of non-social odors. We employed a behavioral assay to characterize the olfactory defects of TBR1 ^ +/− mice. Magnetic resonance imaging (MRI) and histological analysis were applied to characterize anatomical features. Immunostaining was performed to further analyze differences in expression of TBR1 subfamily members (namely TBR1, TBR2, and TBX21), interneuron populations, and dendritic abnormalities in olfactory bulbs. Finally, C-FOS staining was used to monitor neuronal activation of the olfactory system upon odor stimulation. Results TBR1 ^ +/− mice exhibited smaller olfactory bulbs and anterior commissures, reduced interneuron populations, and an abnormal dendritic morphology of mitral cells in the olfactory bulbs. TBR1 haploinsufficiency specifically impaired olfactory discrimination but not olfactory sensation. Neuronal activation upon odorant stimulation was reduced in the glomerular layer of TBR1 ^ +/− olfactory bulbs. Furthermore, although the sizes of piriform and perirhinal cortices were not affected by TBR1 deficiency, neuronal activation was reduced in these two cortical regions in response to odorant stimulation. These results suggest an impairment of neuronal activation in olfactory bulbs and defective connectivity from olfactory bulbs to the upper olfactory system in TBR1 ^ +/− mice. Systemic administration of D-cycloserine, an NMDAR co-agonist, ameliorated olfactory discrimination in TBR1 ^ +/− mice, suggesting that increased neuronal activity has a beneficial effect on TBR1 deficiency. Conclusions TBR1 regulates neural circuits and activity in the olfactory system to control olfaction. TBR1 ^ +/− mice can serve as a suitable model for revealing how an autism causative gene controls neuronal circuits, neural activity, and autism-related behaviors.
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haploinsufficiency of autism causative gene TBR1 impairs olfactory discrimination and neuronal activation of the olfactory system in mice
Molecular Autism, 2019Co-Authors: Tzyy-nan Huang, Tzu-li Yen, Lily R. Qiu, Hsiu-chun Chuang, Jason P. Lerch, Yi-ping HsuehAbstract:Background Autism spectrum disorders (ASD) exhibit two clusters of core symptoms, i.e., social and communication impairment, and repetitive behaviors and sensory abnormalities. Our previous study demonstrated that TBR1, a causative gene of ASD, controls axonal projection and neuronal activation of amygdala and regulates social interaction and vocal communication in a mouse model. Behavioral defects caused by TBR1 haploinsufficiency can be ameliorated by increasing neural activity via D-cycloserine treatment, an N-methyl-D-aspartate receptor (NMDAR) coagonist. In this report, we investigate the role of TBR1 in regulating olfaction and test whether D-cycloserine can also improve olfactory defects in TBR1 mutant mice.
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Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with T-Brain-1 (TBR1) to control extinction of associative memory in male mice.
Journal of psychiatry & neuroscience : JPN, 2017Co-Authors: Tzyy-nan Huang, Yi-ping HsuehAbstract:BACKGROUND Human genetic studies have indicated that mutations in calcium/calmodulin-dependent serine protein kinase (CASK) result in X-linked mental retardation and autism-spectrum disorders. We aimed to establish a mouse model to study how Cask regulates mental ability. METHODS Because Cask encodes a multidomain scaffold protein, a possible strategy to dissect how CASK regulates mental ability and cognition is to disrupt specific protein-protein interactions of CASK in vivo and then investigate the impact of individual specific protein interactions. Previous in vitro analyses indicated that a rat CASK T724A mutation reduces the interaction between CASK and T-brain-1 (TBR1) in transfected COS cells. Because TBR1 is critical for glutamate receptor, ionotropic, N-methyl-D-aspartate receptor subunit 2B (Grin2b) expression and is a causative gene for autism and intellectual disability, we then generated CASK T740A (corresponding to rat CASK T724A) mutant mice using a gene-targeting approach. Immunoblotting, coimmunoprecipitation, histological methods and behavioural assays (including home cage, open field, auditory and contextual fear conditioning and conditioned taste aversion) were applied to investigate expression of CASK and its related proteins, the protein-protein interactions of CASK, and anatomic and behavioural features of CASK T740A mice. RESULTS The CASK T740A mutation attenuated the interaction between CASK and TBR1 in the brain. However, CASK T740A mice were generally healthy, without obvious defects in brain morphology. The most dramatic defect among the mutant mice was in extinction of associative memory, though acquisition was normal. LIMITATIONS The functions of other CASK protein interactions cannot be addressed using CASK T740A mice. CONCLUSION Disruption of the CASK and TBR1 interaction impairs extinction, suggesting the involvement of CASK in cognitive flexibility.
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calcium calmodulin dependent serine protein kinase cask a protein implicated in mental retardation and autism spectrum disorders interacts with t brain 1 TBR1 to control extinction of associative memory in male mice
Journal of Psychiatry & Neuroscience, 2017Co-Authors: Tzyy-nan Huang, Yi-ping HsuehAbstract:BACKGROUND Human genetic studies have indicated that mutations in calcium/calmodulin-dependent serine protein kinase (CASK) result in X-linked mental retardation and autism-spectrum disorders. We aimed to establish a mouse model to study how Cask regulates mental ability. METHODS Because Cask encodes a multidomain scaffold protein, a possible strategy to dissect how CASK regulates mental ability and cognition is to disrupt specific protein-protein interactions of CASK in vivo and then investigate the impact of individual specific protein interactions. Previous in vitro analyses indicated that a rat CASK T724A mutation reduces the interaction between CASK and T-brain-1 (TBR1) in transfected COS cells. Because TBR1 is critical for glutamate receptor, ionotropic, N-methyl-D-aspartate receptor subunit 2B (Grin2b) expression and is a causative gene for autism and intellectual disability, we then generated CASK T740A (corresponding to rat CASK T724A) mutant mice using a gene-targeting approach. Immunoblotting, coimmunoprecipitation, histological methods and behavioural assays (including home cage, open field, auditory and contextual fear conditioning and conditioned taste aversion) were applied to investigate expression of CASK and its related proteins, the protein-protein interactions of CASK, and anatomic and behavioural features of CASK T740A mice. RESULTS The CASK T740A mutation attenuated the interaction between CASK and TBR1 in the brain. However, CASK T740A mice were generally healthy, without obvious defects in brain morphology. The most dramatic defect among the mutant mice was in extinction of associative memory, though acquisition was normal. LIMITATIONS The functions of other CASK protein interactions cannot be addressed using CASK T740A mice. CONCLUSION Disruption of the CASK and TBR1 interaction impairs extinction, suggesting the involvement of CASK in cognitive flexibility.
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Brain-specific transcriptional regulator T-brain-1 controls brain wiring and neuronal activity in autism spectrum disorders.
Frontiers in neuroscience, 2015Co-Authors: Tzyy-nan Huang, Yi-ping HsuehAbstract:T-brain-1 (TBR1) is a brain-specific T-box transcription factor. In 1995, TBR1 was first identified from a subtractive hybridization that compared mouse embryonic and adult telencephalons. Previous studies of TBR1 (-∕-) mice have indicated critical roles for TBR1 in the development of the cerebral cortex, amygdala, and olfactory bulb. Neuronal migration and axonal projection are two important developmental features controlled by TBR1. Recently, recurrent de novo disruptive mutations in the TBR1 gene have been found in patients with autism spectrum disorders (ASDs). Human genetic studies have identified TBR1 as a high-confidence risk factor for ASDs. Because only one allele of the TBR1 gene is mutated in these patients, TBR1 (+∕-) mice serve as a good genetic mouse model to explore the mechanism by which de novo TBR1 mutation leads to ASDs. Although neuronal migration and axonal projection defects of cerebral cortex are the most prominent phenotypes in TBR1 (-∕-) mice, these features are not found in TBR1 (+∕-) mice. Instead, inter- and intra-amygdalar axonal projections and NMDAR expression and activity in amygdala are particularly susceptible to TBR1 haploinsufficiency. The studies indicated that both abnormal brain wiring (abnormal amygdalar connections) and excitation/inhibition imbalance (NMDAR hypoactivity), two prominent models for ASD etiology, are present in TBR1 (+∕-) mice. Moreover, calcium/calmodulin-dependent serine protein kinase (CASK) was found to interact with TBR1. The CASK-TBR1 complex had been shown to directly bind the promoter of the Grin2b gene, which is also known as Nmdar2b, and upregulate Grin2b expression. This molecular function of TBR1 provides an explanation for NMDAR hypoactivity in TBR1 (+∕-) mice. In addition to Grin2b, cell adhesion molecules-including Ntng1, Cdh8, and Cntn2-are also regulated by TBR1 to control axonal projections of amygdala. Taken together, the studies of TBR1 provide an integrated picture of ASD etiology at the cellular and circuit levels.
Robert F. Hevner - One of the best experts on this subject based on the ideXlab platform.
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The Epigenetic Factor Landscape of Developing Neocortex Is Regulated by Transcription Factors Pax6→ Tbr2→ TBR1.
Frontiers in neuroscience, 2018Co-Authors: Gina E Elsen, John L R Rubenstein, Francesco Bedogni, Rebecca D Hodge, Theo K Bammler, James W. Macdonald, Susan Lindtner, Robert F. HevnerAbstract:Epigenetic factors (EFs) regulate multiple aspects of cerebral cortex development, including proliferation, differentiation, laminar fate, and regional identity. The same neurodevelopmental processes are also regulated by transcription factors (TFs), notably the Pax6→ Tbr2→ TBR1 cascade expressed sequentially in radial glial progenitors (RGPs), intermediate progenitors, and postmitotic projection neurons, respectively. Here, we studied the EF landscape and its regulation in embryonic mouse neocortex. Microarray and in situ hybridization assays revealed that many EF genes are expressed in specific cortical cell types, such as intermediate progenitors, or in rostrocaudal gradients. Furthermore, many EF genes are directly bound and transcriptionally regulated by Pax6, Tbr2, or TBR1, as determined by chromatin immunoprecipitation-sequencing and gene expression analysis of TF mutant cortices. Our analysis demonstrated that Pax6, Tbr2, and TBR1 form a direct feedforward genetic cascade, with direct feedback repression. Results also revealed that each TF regulates multiple EF genes that control DNA methylation, histone marks, chromatin remodeling, and non-coding RNA. For example, TBR1 activates Rybp and Auts2 to promote the formation of non-canonical Polycomb repressive complex 1 (PRC1). Also, Pax6, Tbr2, and TBR1 collectively drive massive changes in the subunit isoform composition of BAF chromatin remodeling complexes during differentiation: for example, a novel switch from Bcl7c (Baf40c) to Bcl7a (Baf40a), the latter directly activated by Tbr2. Of 11 subunits predominantly in neuronal BAF, 7 were transcriptionally activated by Pax6, Tbr2, or TBR1. Using EFs, Pax6→ Tbr2→ TBR1 effect persistent changes of gene expression in cell lineages, to propagate features such as regional and laminar identity from progenitors to neurons.
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Control of Neuronal Development by T-Box Genes in the Brain.
Current topics in developmental biology, 2016Co-Authors: Anca B. Mihalas, Robert F. HevnerAbstract:Abstract T-box transcription factors play key roles in the regulation of developmental processes such as cell differentiation and migration. Mammals have 17 T-box genes, of which several regulate brain development. The TBR1 subfamily of T-box genes is particularly important in development of the cerebral cortex, olfactory bulbs (OBs), and cerebellum. This subfamily is comprised of TBR1 , Tbr2 (also known as Eomes ), and Tbx21 . In developing cerebral cortex, Tbr2 and TBR1 are expressed during successive stages of differentiation in the pyramidal neuron lineage, from Tbr2 + intermediate progenitors to TBR1 + postmitotic glutamatergic neurons. At each stage, Tbr2 and TBR1 regulate laminar and regional identity of cortical projection neurons, cell migration, and axon guidance. In the OB, TBR1 subfamily genes regulate neurogenesis of mitral and tufted cells, and glutamatergic juxtaglomerular interneurons. Tbr2 is also prominent in the development of retinal ganglion cells in nonimage-forming pathways. Other regions that require Tbr2 or TBR1 in development or adulthood include the cerebellum and adult dentate gyrus. In humans, de novo mutations in TBR1 are important causes of sporadic autism and intellectual disability. Further studies of T-box transcription factors will enhance our understanding of neurodevelopmental disorders and inform approaches to new therapies.
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Distinct calcium signals in developing cortical interneurons persist despite disorganization of cortex by TBR1 KO
Developmental neurobiology, 2015Co-Authors: Curtis R. Easton, C. W. Dickey, Samantha P. Moen, K. E. Neuzil, Zeke Barger, Tatiana M. Anderson, William J. Moody, Robert F. HevnerAbstract:Cortical development involves the structuring of network features by genetically programmed molecular signaling pathways. Additionally, spontaneous ion channel activity refines neuronal connections. We examine Ca(2+) fluctuations in the first postnatal week of normal mouse neocortex and that expressing knockout of the transcription factor T-brain-1 (TBR1): a signaling molecule in cortical patterning and differentiation of excitatory neurons. In cortex, glutamatergic neurons express TBR1 just before the onset of population electrical activity that is accompanied by intracellular Ca(2+) increases. It is known that glutamatergic cells are disordered with TBR1 KO such that normal laying of the cortex, with newer born cells residing in superficial layers, does not occur. However, the fate of cortical interneurons is not well studied, nor is the ability of TBR1 deficient cortex to express normal physiological activity. Using fluorescent proteins targeted to interneurons, we find that cortical interneurons are also disordered in the TBR1 knockout. Using Ca(2+) imaging we find that population activity in mutant cortex occurs at normal frequencies with similar sensitivity to GABAA receptor blockade as in nonmutant cortex. Finally, using multichannel fluorescence imaging of Ca(2+) indicator dye and interneurons labeled with red fluorescent protein, we identify an additional Ca(2+) signal in interneurons distinct from population activity and with different pharmacological sensitivities. Our results show the population activity described here is a robust property of the developing network that continues in the absence of an important signaling molecule, TBR1, and that cortical interneurons generate distinct forms of activity that may serve different developmental functions. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 705-720, 2016.
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TBR1 regulates regional and laminar identity of postmitotic neurons in developing neocortex
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Francesco Bedogni, John L R Rubenstein, Rebecca D Hodge, Gina E Elsen, Branden R Nelson, Ray A M Daza, Richard P Beyer, Theo K Bammler, Robert F. HevnerAbstract:Areas and layers of the cerebral cortex are specified by genetic programs that are initiated in progenitor cells and then, implemented in postmitotic neurons. Here, we report that TBR1, a transcription factor expressed in postmitotic projection neurons, exerts positive and negative control over both regional (areal) and laminar identity. TBR1 null mice exhibited profound defects of frontal cortex and layer 6 differentiation, as indicated by down-regulation of gene-expression markers such as Bcl6 and Cdh9. Conversely, genes that implement caudal cortex and layer 5 identity, such as Bhlhb5 and Fezf2, were up-regulated in TBR1 mutants. TBR1 implements frontal identity in part by direct promoter binding and activation of Auts2, a frontal cortex gene implicated in autism. TBR1 regulates laminar identity in part by downstream activation or maintenance of Sox5, an important transcription factor controlling neuronal migration and corticofugal axon projections. Similar to Sox5 mutants, TBR1 mutants exhibit ectopic axon projections to the hypothalamus and cerebral peduncle. Together, our findings show that TBR1 coordinately regulates regional and laminar identity of postmitotic cortical neurons.
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Development of the deep cerebellar nuclei: transcription factors and cell migration from the rhombic lip.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2006Co-Authors: Andrew J. Fink, Ray A M Daza, Chris Englund, Diane Pham, Charmaine Lau, Mary Nivison, Tom Kowalczyk, Robert F. HevnerAbstract:The deep cerebellar nuclei (DCN) are the main output centers of the cerebellum, but little is known about their development. Using transcription factors as cell type-specific markers, we found that DCN neurons in mice are produced in the rhombic lip and migrate rostrally in a subpial stream to the nuclear transitory zone (NTZ). The rhombic lip-derived cells express transcription factors Pax6, Tbr2, and TBR1 sequentially as they enter the NTZ. A subset of rhombic lip-derived cells also express reelin, a key regulator of Purkinje cell migrations. In organotypic slice cultures, the rhombic lip was necessary and sufficient to produce cells that migrate in the subpial stream, enter the NTZ, and express Pax6, Tbr2, TBR1, and reelin. In later stages of development, the subpial stream is replaced by the external granular layer, and the NTZ organizes into distinct DCN nuclei. TBR1 expression persists to adulthood in a subset of medial DCN projection neurons. In reeler mutant mice, which have a severe cerebellar malformation, rhombic lip-derived cells migrated to the NTZ, despite reelin deficiency. Studies in TBR1 mutant mice suggested that TBR1 plays a role in DCN morphogenesis but is not required for reelin expression, glutamatergic differentiation, or the initial formation of efferent axon pathways. Our findings reveal underlying similarities in the transcriptional programs for glutamatergic neuron production in the DCN and the cerebral cortex, and they support a model of cerebellar neurogenesis in which glutamatergic and GABAergic neurons are produced from separate progenitor compartments.
John L R Rubenstein - One of the best experts on this subject based on the ideXlab platform.
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Enhancing WNT Signaling Restores Cortical Neuronal Spine Maturation and Synaptogenesis in TBR1 Mutants.
eScholarship University of California, 2020Co-Authors: Fazel Darbandi Siavash, Robinson Schwartz, Sarah E, Pai, Emily Ling-lin, Everitt Amanda, Turner, Marc L, Benjamin Nr Cheyette, Willsey A Jeremy, State, Matthew W, Sohal, Vikaas S, John L R RubensteinAbstract:TBR1 is a high-confidence autism spectrum disorder (ASD) gene encoding a transcription factor with distinct pre- and postnatal functions. Postnatally, TBR1 conditional knockout (CKO) mutants and constitutive heterozygotes have immature dendritic spines and reduced synaptic density. TBR1 regulates expression of several genes that underlie synaptic defects, including a kinesin (Kif1a) and a WNT-signaling ligand (Wnt7b). Furthermore, TBR1 mutant corticothalamic neurons have reduced thalamic axonal arborization. LiCl and a GSK3β inhibitor, two WNT-signaling agonists, robustly rescue the dendritic spines and the synaptic and axonal defects, suggesting that this could have relevance for therapeutic approaches in some forms of ASD
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The Epigenetic Factor Landscape of Developing Neocortex Is Regulated by Transcription Factors Pax6→ Tbr2→ TBR1.
Frontiers in neuroscience, 2018Co-Authors: Gina E Elsen, John L R Rubenstein, Francesco Bedogni, Rebecca D Hodge, Theo K Bammler, James W. Macdonald, Susan Lindtner, Robert F. HevnerAbstract:Epigenetic factors (EFs) regulate multiple aspects of cerebral cortex development, including proliferation, differentiation, laminar fate, and regional identity. The same neurodevelopmental processes are also regulated by transcription factors (TFs), notably the Pax6→ Tbr2→ TBR1 cascade expressed sequentially in radial glial progenitors (RGPs), intermediate progenitors, and postmitotic projection neurons, respectively. Here, we studied the EF landscape and its regulation in embryonic mouse neocortex. Microarray and in situ hybridization assays revealed that many EF genes are expressed in specific cortical cell types, such as intermediate progenitors, or in rostrocaudal gradients. Furthermore, many EF genes are directly bound and transcriptionally regulated by Pax6, Tbr2, or TBR1, as determined by chromatin immunoprecipitation-sequencing and gene expression analysis of TF mutant cortices. Our analysis demonstrated that Pax6, Tbr2, and TBR1 form a direct feedforward genetic cascade, with direct feedback repression. Results also revealed that each TF regulates multiple EF genes that control DNA methylation, histone marks, chromatin remodeling, and non-coding RNA. For example, TBR1 activates Rybp and Auts2 to promote the formation of non-canonical Polycomb repressive complex 1 (PRC1). Also, Pax6, Tbr2, and TBR1 collectively drive massive changes in the subunit isoform composition of BAF chromatin remodeling complexes during differentiation: for example, a novel switch from Bcl7c (Baf40c) to Bcl7a (Baf40a), the latter directly activated by Tbr2. Of 11 subunits predominantly in neuronal BAF, 7 were transcriptionally activated by Pax6, Tbr2, or TBR1. Using EFs, Pax6→ Tbr2→ TBR1 effect persistent changes of gene expression in cell lineages, to propagate features such as regional and laminar identity from progenitors to neurons.
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TBR1 instructs laminar patterning of retinal ganglion cell dendrites
Nature Neuroscience, 2018Co-Authors: Jinyue Liu, John L R Rubenstein, Bin Chen, Jasmine D S Reggiani, Mallory A Laboulaye, Shristi Pandey, Arjun Krishnaswamy, Joshua R SanesAbstract:Specific retinal connectivity depends on laminar restriction of neuronal processes. The authors show that a single transcription factor specifies a common laminar identity in dendrites of four retinal cell types, albeit via cell-type-specific means. Visual information is delivered to the brain by >40 types of retinal ganglion cells (RGCs). Diversity in this representation arises within the inner plexiform layer (IPL), where dendrites of each RGC type are restricted to specific sublaminae, limiting the interneuronal types that can innervate them. How such dendritic restriction arises is unclear. We show that the transcription factor TBR1 is expressed by four mouse RGC types with dendrites in the outer IPL and is required for their laminar specification. Loss of TBR1 results in elaboration of dendrites within the inner IPL, while misexpression in other cells retargets their neurites to the outer IPL. Two transmembrane molecules, Sorcs3 and Cdh8, act as effectors of the TBR1-controlled lamination program. However, they are expressed in just one TBR1^+ RGC type, supporting a model in which a single transcription factor implements similar laminar choices in distinct cell types by recruiting partially non-overlapping effectors.
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TBR1 instructs laminar patterning of retinal ganglion cell dendrites
Nature Neuroscience, 2018Co-Authors: Jasmine D S Reggiani, John L R Rubenstein, Bin Chen, Mallory A Laboulaye, Shristi Pandey, Arjun Krishnaswamy, Joshua R SanesAbstract:Visual information is delivered to the brain by >40 types of retinal ganglion cells (RGCs). Diversity in this representation arises within the inner plexiform layer (IPL), where dendrites of each RGC type are restricted to specific sublaminae, limiting the interneuronal types that can innervate them. How such dendritic restriction arises is unclear. We show that the transcription factor TBR1 is expressed by four mouse RGC types with dendrites in the outer IPL and is required for their laminar specification. Loss of TBR1 results in elaboration of dendrites within the inner IPL, while misexpression in other cells retargets their neurites to the outer IPL. Two transmembrane molecules, Sorcs3 and Cdh8, act as effectors of the TBR1-controlled lamination program. However, they are expressed in just one TBR1+ RGC type, supporting a model in which a single transcription factor implements similar laminar choices in distinct cell types by recruiting partially non-overlapping effectors.
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TBR1 regulates autism risk genes in the developing neocortex.
Genome research, 2016Co-Authors: James H. Notwell, John L R Rubenstein, Whitney E. Heavner, Siavash Fazel Darbandi, Sol Katzman, William L. Mckenna, Christian F. Ortiz-londono, David Tastad, Matthew J. Eckler, Susan K McconnellAbstract:Exome sequencing studies have identified multiple genes harboring de novo loss-of-function (LoF) variants in individuals with autism spectrum disorders (ASD), including TBR1, a master regulator of cortical development. We performed ChIP-seq for TBR1 during mouse cortical neurogenesis and show that TBR1-bound regions are enriched adjacent to ASD genes. ASD genes were also enriched among genes that are differentially expressed in TBR1 knockouts, which together with the ChIP-seq data, suggests direct transcriptional regulation. Of the nine ASD genes examined, seven were misexpressed in the cortices of TBR1 knockout mice, including six with increased expression in the deep cortical layers. ASD genes with adjacent cortical TBR1 ChIP-seq peaks also showed unusually low levels of LoF mutations in a reference human population and among Icelanders. We then leveraged TBR1 binding to identify an appealing subset of candidate ASD genes. Our findings highlight a TBR1-regulated network of ASD genes in the developing neocortex that are relatively intolerant to LoF mutations, indicating that these genes may play critical roles in normal cortical development.
Tzyy-nan Huang - One of the best experts on this subject based on the ideXlab platform.
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Haploinsufficiency of autism causative gene TBR1 impairs olfactory discrimination and neuronal activation of the olfactory system in mice
Molecular Autism, 2019Co-Authors: Tzyy-nan Huang, Tzu-li Yen, Lily R. Qiu, Hsiu-chun Chuang, Jason P. Lerch, Yi-ping HsuehAbstract:Background Autism spectrum disorders (ASD) exhibit two clusters of core symptoms, i.e., social and communication impairment, and repetitive behaviors and sensory abnormalities. Our previous study demonstrated that TBR1, a causative gene of ASD, controls axonal projection and neuronal activation of amygdala and regulates social interaction and vocal communication in a mouse model. Behavioral defects caused by TBR1 haploinsufficiency can be ameliorated by increasing neural activity via D-cycloserine treatment, an N-methyl-D-aspartate receptor (NMDAR) coagonist. In this report, we investigate the role of TBR1 in regulating olfaction and test whether D-cycloserine can also improve olfactory defects in TBR1 mutant mice. Methods We used TBR1 ^ +/− mice as a model to investigate the function of TBR1 in olfactory sensation and discrimination of non-social odors. We employed a behavioral assay to characterize the olfactory defects of TBR1 ^ +/− mice. Magnetic resonance imaging (MRI) and histological analysis were applied to characterize anatomical features. Immunostaining was performed to further analyze differences in expression of TBR1 subfamily members (namely TBR1, TBR2, and TBX21), interneuron populations, and dendritic abnormalities in olfactory bulbs. Finally, C-FOS staining was used to monitor neuronal activation of the olfactory system upon odor stimulation. Results TBR1 ^ +/− mice exhibited smaller olfactory bulbs and anterior commissures, reduced interneuron populations, and an abnormal dendritic morphology of mitral cells in the olfactory bulbs. TBR1 haploinsufficiency specifically impaired olfactory discrimination but not olfactory sensation. Neuronal activation upon odorant stimulation was reduced in the glomerular layer of TBR1 ^ +/− olfactory bulbs. Furthermore, although the sizes of piriform and perirhinal cortices were not affected by TBR1 deficiency, neuronal activation was reduced in these two cortical regions in response to odorant stimulation. These results suggest an impairment of neuronal activation in olfactory bulbs and defective connectivity from olfactory bulbs to the upper olfactory system in TBR1 ^ +/− mice. Systemic administration of D-cycloserine, an NMDAR co-agonist, ameliorated olfactory discrimination in TBR1 ^ +/− mice, suggesting that increased neuronal activity has a beneficial effect on TBR1 deficiency. Conclusions TBR1 regulates neural circuits and activity in the olfactory system to control olfaction. TBR1 ^ +/− mice can serve as a suitable model for revealing how an autism causative gene controls neuronal circuits, neural activity, and autism-related behaviors.
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haploinsufficiency of autism causative gene TBR1 impairs olfactory discrimination and neuronal activation of the olfactory system in mice
Molecular Autism, 2019Co-Authors: Tzyy-nan Huang, Tzu-li Yen, Lily R. Qiu, Hsiu-chun Chuang, Jason P. Lerch, Yi-ping HsuehAbstract:Background Autism spectrum disorders (ASD) exhibit two clusters of core symptoms, i.e., social and communication impairment, and repetitive behaviors and sensory abnormalities. Our previous study demonstrated that TBR1, a causative gene of ASD, controls axonal projection and neuronal activation of amygdala and regulates social interaction and vocal communication in a mouse model. Behavioral defects caused by TBR1 haploinsufficiency can be ameliorated by increasing neural activity via D-cycloserine treatment, an N-methyl-D-aspartate receptor (NMDAR) coagonist. In this report, we investigate the role of TBR1 in regulating olfaction and test whether D-cycloserine can also improve olfactory defects in TBR1 mutant mice.
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Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with T-Brain-1 (TBR1) to control extinction of associative memory in male mice.
Journal of psychiatry & neuroscience : JPN, 2017Co-Authors: Tzyy-nan Huang, Yi-ping HsuehAbstract:BACKGROUND Human genetic studies have indicated that mutations in calcium/calmodulin-dependent serine protein kinase (CASK) result in X-linked mental retardation and autism-spectrum disorders. We aimed to establish a mouse model to study how Cask regulates mental ability. METHODS Because Cask encodes a multidomain scaffold protein, a possible strategy to dissect how CASK regulates mental ability and cognition is to disrupt specific protein-protein interactions of CASK in vivo and then investigate the impact of individual specific protein interactions. Previous in vitro analyses indicated that a rat CASK T724A mutation reduces the interaction between CASK and T-brain-1 (TBR1) in transfected COS cells. Because TBR1 is critical for glutamate receptor, ionotropic, N-methyl-D-aspartate receptor subunit 2B (Grin2b) expression and is a causative gene for autism and intellectual disability, we then generated CASK T740A (corresponding to rat CASK T724A) mutant mice using a gene-targeting approach. Immunoblotting, coimmunoprecipitation, histological methods and behavioural assays (including home cage, open field, auditory and contextual fear conditioning and conditioned taste aversion) were applied to investigate expression of CASK and its related proteins, the protein-protein interactions of CASK, and anatomic and behavioural features of CASK T740A mice. RESULTS The CASK T740A mutation attenuated the interaction between CASK and TBR1 in the brain. However, CASK T740A mice were generally healthy, without obvious defects in brain morphology. The most dramatic defect among the mutant mice was in extinction of associative memory, though acquisition was normal. LIMITATIONS The functions of other CASK protein interactions cannot be addressed using CASK T740A mice. CONCLUSION Disruption of the CASK and TBR1 interaction impairs extinction, suggesting the involvement of CASK in cognitive flexibility.
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calcium calmodulin dependent serine protein kinase cask a protein implicated in mental retardation and autism spectrum disorders interacts with t brain 1 TBR1 to control extinction of associative memory in male mice
Journal of Psychiatry & Neuroscience, 2017Co-Authors: Tzyy-nan Huang, Yi-ping HsuehAbstract:BACKGROUND Human genetic studies have indicated that mutations in calcium/calmodulin-dependent serine protein kinase (CASK) result in X-linked mental retardation and autism-spectrum disorders. We aimed to establish a mouse model to study how Cask regulates mental ability. METHODS Because Cask encodes a multidomain scaffold protein, a possible strategy to dissect how CASK regulates mental ability and cognition is to disrupt specific protein-protein interactions of CASK in vivo and then investigate the impact of individual specific protein interactions. Previous in vitro analyses indicated that a rat CASK T724A mutation reduces the interaction between CASK and T-brain-1 (TBR1) in transfected COS cells. Because TBR1 is critical for glutamate receptor, ionotropic, N-methyl-D-aspartate receptor subunit 2B (Grin2b) expression and is a causative gene for autism and intellectual disability, we then generated CASK T740A (corresponding to rat CASK T724A) mutant mice using a gene-targeting approach. Immunoblotting, coimmunoprecipitation, histological methods and behavioural assays (including home cage, open field, auditory and contextual fear conditioning and conditioned taste aversion) were applied to investigate expression of CASK and its related proteins, the protein-protein interactions of CASK, and anatomic and behavioural features of CASK T740A mice. RESULTS The CASK T740A mutation attenuated the interaction between CASK and TBR1 in the brain. However, CASK T740A mice were generally healthy, without obvious defects in brain morphology. The most dramatic defect among the mutant mice was in extinction of associative memory, though acquisition was normal. LIMITATIONS The functions of other CASK protein interactions cannot be addressed using CASK T740A mice. CONCLUSION Disruption of the CASK and TBR1 interaction impairs extinction, suggesting the involvement of CASK in cognitive flexibility.
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Brain-specific transcriptional regulator T-brain-1 controls brain wiring and neuronal activity in autism spectrum disorders.
Frontiers in neuroscience, 2015Co-Authors: Tzyy-nan Huang, Yi-ping HsuehAbstract:T-brain-1 (TBR1) is a brain-specific T-box transcription factor. In 1995, TBR1 was first identified from a subtractive hybridization that compared mouse embryonic and adult telencephalons. Previous studies of TBR1 (-∕-) mice have indicated critical roles for TBR1 in the development of the cerebral cortex, amygdala, and olfactory bulb. Neuronal migration and axonal projection are two important developmental features controlled by TBR1. Recently, recurrent de novo disruptive mutations in the TBR1 gene have been found in patients with autism spectrum disorders (ASDs). Human genetic studies have identified TBR1 as a high-confidence risk factor for ASDs. Because only one allele of the TBR1 gene is mutated in these patients, TBR1 (+∕-) mice serve as a good genetic mouse model to explore the mechanism by which de novo TBR1 mutation leads to ASDs. Although neuronal migration and axonal projection defects of cerebral cortex are the most prominent phenotypes in TBR1 (-∕-) mice, these features are not found in TBR1 (+∕-) mice. Instead, inter- and intra-amygdalar axonal projections and NMDAR expression and activity in amygdala are particularly susceptible to TBR1 haploinsufficiency. The studies indicated that both abnormal brain wiring (abnormal amygdalar connections) and excitation/inhibition imbalance (NMDAR hypoactivity), two prominent models for ASD etiology, are present in TBR1 (+∕-) mice. Moreover, calcium/calmodulin-dependent serine protein kinase (CASK) was found to interact with TBR1. The CASK-TBR1 complex had been shown to directly bind the promoter of the Grin2b gene, which is also known as Nmdar2b, and upregulate Grin2b expression. This molecular function of TBR1 provides an explanation for NMDAR hypoactivity in TBR1 (+∕-) mice. In addition to Grin2b, cell adhesion molecules-including Ntng1, Cdh8, and Cntn2-are also regulated by TBR1 to control axonal projections of amygdala. Taken together, the studies of TBR1 provide an integrated picture of ASD etiology at the cellular and circuit levels.
Hsiu-chun Chuang - One of the best experts on this subject based on the ideXlab platform.
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Haploinsufficiency of autism causative gene TBR1 impairs olfactory discrimination and neuronal activation of the olfactory system in mice
Molecular Autism, 2019Co-Authors: Tzyy-nan Huang, Tzu-li Yen, Lily R. Qiu, Hsiu-chun Chuang, Jason P. Lerch, Yi-ping HsuehAbstract:Background Autism spectrum disorders (ASD) exhibit two clusters of core symptoms, i.e., social and communication impairment, and repetitive behaviors and sensory abnormalities. Our previous study demonstrated that TBR1, a causative gene of ASD, controls axonal projection and neuronal activation of amygdala and regulates social interaction and vocal communication in a mouse model. Behavioral defects caused by TBR1 haploinsufficiency can be ameliorated by increasing neural activity via D-cycloserine treatment, an N-methyl-D-aspartate receptor (NMDAR) coagonist. In this report, we investigate the role of TBR1 in regulating olfaction and test whether D-cycloserine can also improve olfactory defects in TBR1 mutant mice. Methods We used TBR1 ^ +/− mice as a model to investigate the function of TBR1 in olfactory sensation and discrimination of non-social odors. We employed a behavioral assay to characterize the olfactory defects of TBR1 ^ +/− mice. Magnetic resonance imaging (MRI) and histological analysis were applied to characterize anatomical features. Immunostaining was performed to further analyze differences in expression of TBR1 subfamily members (namely TBR1, TBR2, and TBX21), interneuron populations, and dendritic abnormalities in olfactory bulbs. Finally, C-FOS staining was used to monitor neuronal activation of the olfactory system upon odor stimulation. Results TBR1 ^ +/− mice exhibited smaller olfactory bulbs and anterior commissures, reduced interneuron populations, and an abnormal dendritic morphology of mitral cells in the olfactory bulbs. TBR1 haploinsufficiency specifically impaired olfactory discrimination but not olfactory sensation. Neuronal activation upon odorant stimulation was reduced in the glomerular layer of TBR1 ^ +/− olfactory bulbs. Furthermore, although the sizes of piriform and perirhinal cortices were not affected by TBR1 deficiency, neuronal activation was reduced in these two cortical regions in response to odorant stimulation. These results suggest an impairment of neuronal activation in olfactory bulbs and defective connectivity from olfactory bulbs to the upper olfactory system in TBR1 ^ +/− mice. Systemic administration of D-cycloserine, an NMDAR co-agonist, ameliorated olfactory discrimination in TBR1 ^ +/− mice, suggesting that increased neuronal activity has a beneficial effect on TBR1 deficiency. Conclusions TBR1 regulates neural circuits and activity in the olfactory system to control olfaction. TBR1 ^ +/− mice can serve as a suitable model for revealing how an autism causative gene controls neuronal circuits, neural activity, and autism-related behaviors.
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haploinsufficiency of autism causative gene TBR1 impairs olfactory discrimination and neuronal activation of the olfactory system in mice
Molecular Autism, 2019Co-Authors: Tzyy-nan Huang, Tzu-li Yen, Lily R. Qiu, Hsiu-chun Chuang, Jason P. Lerch, Yi-ping HsuehAbstract:Background Autism spectrum disorders (ASD) exhibit two clusters of core symptoms, i.e., social and communication impairment, and repetitive behaviors and sensory abnormalities. Our previous study demonstrated that TBR1, a causative gene of ASD, controls axonal projection and neuronal activation of amygdala and regulates social interaction and vocal communication in a mouse model. Behavioral defects caused by TBR1 haploinsufficiency can be ameliorated by increasing neural activity via D-cycloserine treatment, an N-methyl-D-aspartate receptor (NMDAR) coagonist. In this report, we investigate the role of TBR1 in regulating olfaction and test whether D-cycloserine can also improve olfactory defects in TBR1 mutant mice.
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T-Brain-1--A Potential Master Regulator in Autism Spectrum Disorders.
Autism research : official journal of the International Society for Autism Research, 2015Co-Authors: Hsiu-chun Chuang, Tzyy-nan Huang, Yi-ping HsuehAbstract:T-Brain-1 (TBR1), a causative gene in autism spectrum disorders (ASDs), encodes a brain-specific T-box transcription factor. It is therefore possible that TBR1 controls the expression of other autism risk factors. The downstream genes of TBR1 have been identified using microarray and promoter analyses. In this study, we annotated individual genes downstream of TBR1 and investigated any associations with ASDs through extensive literature searches. Of 124 TBR1 target genes, 23 were reported to be associated with ASDs. In addition, one gene, Kiaa0319, is a known causative gene for dyslexia, a disorder frequently associated with autism. A change in expression level in 10 of these 24 genes has been previously confirmed. We further validated the alteration of RNA expression levels of Kiaa0319, Baiap2, and Gad1 in TBR1 deficient mice. Among these 24 genes, four transcription factors Auts2, Nfia, Nr4a2, and Sox5 were found, suggesting that TBR1 controls a transcriptional cascade relevant to autism pathogenesis. A further five of the 24 genes (Cd44, Cdh8, Cntn6, Gpc6, and Ntng1) encode membrane proteins that regulate cell adhesion and axonal outgrowth. These genes likely contribute to the role of TBR1 in regulation of neuronal migration and axonal extension. Besides, decreases in Grin2b expression and increases in Gad1 expression imply that neuronal activity may be aberrant in TBR1 deficient mice. These analyses provide direction for future experiments to reveal the pathogenic mechanism of autism. Autism Res 2015, 8: 412–426. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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Neuronal Excitation Upregulates TBR1, a High-Confidence Risk Gene of Autism, Mediating Grin2b Expression in the Adult Brain
Frontiers in cellular neuroscience, 2014Co-Authors: Hsiu-chun Chuang, Tzyy-nan Huang, Yi-ping HsuehAbstract:The activity-regulated gene expression of transcription factors is required for neural plasticity and function in response to neuronal stimulation. T-brain-1 (TBR1), a critical neuron-specific transcription factor for forebrain development, has been recognized as a high-confidence risk gene for autism spectrum disorders. Here, we show that in addition to its role in brain development, TBR1 responds to neuronal activation and further modulates the Grin2b expression in adult brains and mature neurons. The expression levels of TBR1 were investigated using both immunostaining and quantitative reverse transcription polymerase chain reaction (RT-PCR) analyses. We found that the mRNA and protein expression levels of TBR1 are induced by excitatory synaptic transmission driven by bicuculline or glutamate treatment in cultured mature neurons. The upregulation of TBR1 expression requires the activation of both α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. Furthermore, behavioral training triggers TBR1 induction in the adult mouse brain. The elevation of TBR1 expression is associated with Grin2b upregulation in both mature neurons and adult brains. Using TBR1-deficient neurons, we further demonstrated that TBR1 is required for the induction of Grin2b upon neuronal activation. Taken together with the previous studies showing that TBR1 binds the Grin2b promoter and controls expression of luciferase reporter driven by Grin2b promoter, the evidence suggests that TBR1 directly controls Grin2b expression in mature neurons. We also found that the addition of the calcium/calmodulin-dependent protein kinase II (CaMKII) antagonist KN-93, but not the calcium-dependent phosphatase calcineurin antagonist cyclosporin A, to cultured mature neurons noticeably inhibited TBR1 induction, indicating that neuronal activation upregulates TBR1 expression in a CaMKII-dependent manner. In conclusion, our study suggests that TBR1 plays an important role in adult mouse brains in response to neuronal activation to modulate the activity-regulated gene transcription required for neural plasticity.
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TBR1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality
Nature neuroscience, 2014Co-Authors: Tzyy-nan Huang, Hsiu-chun Chuang, Wen-hsi Chou, Chiung-ya Chen, Hsiao-fang Wang, Shen-ju Chou, Yi-ping HsuehAbstract:The authors show that mice lacking one copy of gene encoding the transcription factor T-box brain 1 (TBR1) show deficient axonal projections from amygdala neurons, as well as social and cognitive behavioral deficits. TBR1 haploinsufficiency alters expression of multiple TBR1 target genes, and restoring their expression restores axon outgrowth defects in vivo.
