Role of Tet1/3 Genes and Chromatin Remodeling Genes in Cerebellar Circuit Formation

Zhu, Xiaodong; Girardo, David; Govek, Eve-Ellen; John, Keisha; Mellén, Marian; Tamayo, Pablo; Mesirov, Jill P.; Hatten, Mary E.

doi:10.1016/j.neuron.2015.11.030

Cited by 74 publications

(98 citation statements)

References 53 publications

(94 reference statements)

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“…We identified seven novel candidate ARID genes, CACNG7, CARNMT1 / C9orf41, EI24, FXR1, TET3, GARNL3 and TRAPPC10 , for which evidence of their contribution to the corresponding ARID phenotype is strong (Table 5). For novel genes EI24, FXR1 and TET3 a role in ARID is strongly supported by observations in previously published knockout mouse models: Ei24 −/− and Tet3 −/− mice demonstrate defects in brain morphology, neuronal differentiation and/or behavior and motor development, while the Fxr1 knockout results in early death, with lower brain miRNA expression in Fxr1 −/− embryos (Zhao et al 2012; Zhu et al 2016; Xu et al. 2011; Table 5).…”

Section: Discussionsupporting

confidence: 69%

Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability

Santos‐Cortez

Khan

et al. 2018

Hum Genet

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Identification of Mendelian genes for neurodevelopmental disorders using exome sequencing to study autosomal recessive (AR) consanguineous pedigrees has been highly successful. To identify causal variants for syndromic and non-syndromic intellectual disability (ID), exome sequencing was performed using DNA samples from 22 consanguineous Pakistani families with ARID, of which 21 have additional phenotypes including microcephaly. To aid in variant identification, homozygosity mapping and linkage analysis were performed. DNA samples from affected family member(s) from every pedigree underwent exome sequencing. Identified rare damaging exome variants were tested for co-segregation with ID using Sanger sequencing. For seven ARID families, variants were identified in genes not previously associated with ID, including: EI24, FXR1 and TET3 for which knockout mouse models have brain defects; and CACNG7 and TRAPPC10 where cell studies suggest roles in important neural pathways. For two families, the novel ARID genes CARNMT1 and GARNL3 lie within previously reported ID microdeletion regions. We also observed homozygous variants in two ID candidate genes, GRAMD1B and TBRG1, for which each has been previously reported in a single family. An additional 14 families have homozygous variants in established ID genes, of which 11 variants are novel. All ARID genes have increased expression in specific structures of the developing and adult human brain and 91% of the genes are differentially expressed in utero or during early childhood. The identification of novel ARID candidate genes and variants adds to the knowledge base that is required to further understand human brain function and development.

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Section: Discussionsupporting

confidence: 69%

Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability

Santos‐Cortez

Khan

et al. 2018

Hum Genet

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“…In addition to adhesion, CGNs provide an excellent model system to study the cell biological underpinnings of neural development due to their strongly stereotyped developmental programs as they differentiate from cerebellar granule neuron progenitors (GNPs) (75). Intrinsic to this process is the 3D structural reorganization of their nuclear chromatin domains (76,77). To explore this in detail, we first used 3D live cell lattice light sheet microscopy (LLSM) (78) and found that flow sorted GNPs expressing the EGFP-Atoh1 marker of the GNP-state (79, 80) possess significantly larger nuclei than terminally differentiated CGNs ( Figure 7A, B, supplementary note 10).…”

Section: Chromatin Domains and Their Reorganization During Neuronal Dmentioning

confidence: 99%

Correlative three-dimensional super-resolution and block face electron microscopy of whole vitreously frozen cells

Hoffman

Shtengel

et al. 2019

Preprint

119

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words):Living cells function through the spatial compartmentalization of thousands of distinct proteins serving a multitude of diverse biochemical needs. Correlative super-resolution (SR) fluorescence and electron microscopy (EM) has emerged as a pathway to directly view nanoscale protein relationships to the underlying global ultrastructure, but has traditionally suffered from tradeoffs of structure preservation, fluorescence retention, resolution, and field of view. We developed a platform for three-dimensional correlative cryogenic SR and focused ion beam milled block-face EM across entire vitreously frozen cells that addresses these issues by preserving native ultrastructure and enabling independent SR and EM workflow optimization. Application to a variety of biological systems revealed a number of unexpected protein-ultrastructure relationships and underscored the value of a comprehensive multimodal view of ultrastructural variability across whole cells. modalities (supplementary note 1, table S1), allowing specific molecular components to be visualized at nanoscale resolution in the context of the crowded intracellular environment.However, SR/EM correlation often involves tradeoffs in sample preparation between the retention of fluorescent labels, sufficiently dense heavy metal staining for high contrast EM, and faithful preservation of ultrastructure, particularly when chemical fixation is used (19)(20)(21)(22).Here we describe a pipeline ( fig. S1) for correlative cryo-SR/FIB-SEM imaging of whole cells designed to address these issues. Specifically, cryogenic, as opposed to room temperature, SR performed after high pressure freezing (HPF), allowed us to use a standard EM sample preparation protocol without compromise. We used cryogenic 3D structured illumination (SIM) and single molecule localization (SMLM) microscopy for SR protein specific contrast with 3D FIB-SEM for global contrast of subcellular ultrastructure. The SR modality highlights features not readily apparent from the EM data alone, such as exceptionally long or convoluted endosomes, and permits unique classification of vesicles of like morphology, such as lysosomes, peroxisomes, and mitochondrial-derived vesicles. Cell-wide 3D correlation also reveals unexpected localization patterns of proteins, including intranuclear vesicles positive for an ER marker, intricate web-like structures of adhesion proteins at cell-cell junctions, and heterogeneity in euchromatin or heterochromatin recruitment of transcriptionally-associated histone H3.3 and heterochromatin protein 1α (HP1α) in the nuclei of neural progenitor cells as they transition into differentiated neurons). More generally, whole cell cryo-SR/FIB-SEM can reveal compartmentalized proteins within known subcellular components, help discover new subcellular components, and classify unknown EM morphologies and their roles in cell biology. Cryogenic SR below 10K: motivations and photophysical characterization

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“…The TET family includes proteins that are particularly enriched in brain tissue and differentially expressed in neuronal and glial cells (Globisch et al, 2010;Li and Liu, 2011;Szulwach et al, 2011;Zhao et al, 2014). In neuronal progenitors, TETs are necessary for their differentiation during cortical development (Hahn et al, 2013), and later for axonal growth and functional neuronal circuits formation (Weng et al, 2017;Zhu et al, 2016). In glial cells, the functional role of TETs has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

TET1-mediated DNA hydroxy-methylation regulates adult remyelination

Moyon

Frawley

Marshall-Phelps³

et al. 2019

Preprint

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Highlights:-DNA hydroxy-methylation (5hmC) regulates gene expression in adult OPC (aOPC) -TET1, the enzyme catalyzing 5hmC in aOPC regulates myelin regenerative potential -Age-related TET1 decline results in decreased 5hmC and inefficient remyelination -Tet1 loss in aOPC impairs solute carrier expression and mimics remyelination in aging SummaryAdult myelination is essential for brain function and response to injury, but the molecular mechanisms remain elusive. Here we identify DNA hydroxy-methylation, an epigenetic mark catalyzed by Ten-Eleven translocation (TET) enzymes, as necessary for adult myelin repair.While DNA hydroxy-methylation and high levels of TET1 are detected in young adult mice during myelin regeneration after demyelination, this process is defective in old mice. Constitutive or inducible lineage-specific ablation of Tet1 (but not of Tet2) recapitulate the age-related decline of DNA hydroxy-methylation and inefficient remyelination. Genome-wide hydroxy-methylation and transcriptomic analysis identify numerous TET1 targets, including several members of the solute carrier (Slc) gene family. Lower transcripts for Slc genes, including Slc12a2, are observed in Tet1 mutants and old mice and are associated with swelling at the neuroglial interface, a phenotype detected also in zebrafish slc12a2b mutants.We conclude that TET1-mediated DNA hydroxy-methylation is necessary for adult myelination after injury.

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Role of Tet1/3 Genes and Chromatin Remodeling Genes in Cerebellar Circuit Formation

Cited by 74 publications

References 53 publications

Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability

Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability

Correlative three-dimensional super-resolution and block face electron microscopy of whole vitreously frozen cells

TET1-mediated DNA hydroxy-methylation regulates adult remyelination

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