Transcriptional and Post-Transcriptional Mechanisms of the Development of Neocortical Lamination

Popovitchenko, Tatiana; Rašin, Mladen-Roko

doi:10.3389/fnana.2017.00102

Cited by 39 publications

(48 citation statements)

References 186 publications

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“…he mature neocortex generates complex behaviors including high-level cognition and voluntary motor functions. In the prenatal neocortex, neural stem cells called radial glia progenitors (RG) sequentially give rise to distinct subpopulations of glutamatergic neurons that are critical for normal circuits and functions [1][2][3] . RG and glutamatergic neurons execute transcriptional and post-transcriptional programs that drive their development [1][2][3][4][5][6][7] .…”

mentioning

confidence: 99%

“…In the prenatal neocortex, neural stem cells called radial glia progenitors (RG) sequentially give rise to distinct subpopulations of glutamatergic neurons that are critical for normal circuits and functions [1][2][3] . RG and glutamatergic neurons execute transcriptional and post-transcriptional programs that drive their development [1][2][3][4][5][6][7] . Post-transcriptional regulatory programs include alternative splicing of mRNA isoforms that determine cell fate 8 and the regulation of mRNA translation (protein synthesis) 2,3,5,7,[9][10][11][12][13][14][15] .…”

mentioning

confidence: 99%

“…Translational control is facilitated by RNA-binding proteins (RBPs), which often act on regulatory elements found in 5′ and 3′ untranslated regions (UTRs) 3,5,7,[16][17][18] . UTRs are sites where multiple trans-acting factors may compete or cooperate to affect translation 19,20 .…”

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Translational derepression of Elavl4 isoforms at their alternative 5′ UTRs determines neuronal development

et al. 2020

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Neurodevelopment requires precise regulation of gene expression, including posttranscriptional regulatory events such as alternative splicing and mRNA translation. However, translational regulation of specific isoforms during neurodevelopment and the mechanisms behind it remain unknown. Using RNA-seq analysis of mouse neocortical polysomes, here we report translationally repressed and derepressed mRNA isoforms during neocortical neurogenesis whose orthologs include risk genes for neurodevelopmental disorders. We demonstrate that the translation of distinct mRNA isoforms of the RNA binding protein (RBP), Elavl4, in radial glia progenitors and early neurons depends on its alternative 5′ UTRs. Furthermore, 5′ UTR-driven Elavl4 isoform-specific translation depends on upstream control by another RBP, Celf1. Celf1 regulation of Elavl4 translation dictates development of glutamatergic neurons. Our findings reveal a dynamic interplay between distinct RBPs and alternative 5′ UTRs in neuronal development and underscore the risk of post-transcriptional dysregulation in co-occurring neurodevelopmental disorders.

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Translational derepression of Elavl4 isoforms at their alternative 5′ UTRs determines neuronal development

et al. 2020

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“…Large-scale transcriptome and epigenome profiling studies reveal that COs recapitulate many of the key epigenetic and transcriptional programs found in developing human forebrain (54,55). Post-transcriptional regulatory mechanisms play crucial roles in both neocortex development (56)(57)(58) and dosage compensation in DS cells (16). Consequently, trisomy 21 is predicted to have complex effects on proteome remodeling in the developing brain not revealed by steady state mRNA measurements.…”

Section: Introductionmentioning

confidence: 99%

Cerebral organoid proteomics reveals signatures of dysregulated cortical development associated with human trisomy 21

McClure-Begley

Ebmeier

Ball

et al. 2018

Preprint

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RUNNING TITLE: Proteomics of harmine treated trisomy 21 cerebral organoids 2 ABBREVIATIONS: HSA21, human chromosome 21; DS, Down syndrome; CO, cerebral organoid; EB, embryoid body; iPSC, induced pluripotent stem cell; DMSO, dimethyl sulfoxide; EdU, 5-ethynyl-2'-deoxyuridine; FDR, false discovery rate; T21, the trisomy 21 C2-4 iPSC line; D21, the euploid I50-2 iPSC line; TX100, Triton X-100; NS, neurosphere; DPBS, Dulbecco's phosphate-buffered saline; PBS, phosphate-buffered saline; AGC, Automatic Gain Control; LFQ, label-free quantitation; PCA, principal component analysis; ECM, extracellular matrix; WGCNA, weighted gene co-expression network analysis 3 SUMMARY Human trisomy 21 (Down syndrome) is the most common genetic cause of intellectual disability, and is associated with complex perturbations in protein expression during development. Brain region-specific alterations in neuronal density and composition originate prenatally in trisomy 21 individuals, and are presumed to underlie the intellectual disability and early onset neurodegeneration that characterizes Down syndrome. However, the mechanisms by which chromosome 21 aneuploidy drives alterations in the central nervous system are not well understood, particularly in brain regions that are uniquely human and thus inaccessible to established animal models. Cerebral organoids are pluripotent stem cell derived models of prenatal brain development that have been used to deepen our understanding of the atypical processes associated with human neurobiological disorders, and thus provide a promising avenue to explore the molecular basis for neurodevelopmental alterations in trisomy 21. Here, we employ high-resolution label-free mass spectrometry to map proteomic changes over the course of trisomy 21 cerebral organoid development, and evaluate the proteomic alterations in response to treatment with harmine, a small molecule inhibitor of the chromosome 21 encoded protein kinase DYRK1A. Our results reveal trisomy 21 specific dysregulation of networks associated with neurogenesis, axon guidance and extracellular matrix remodeling. We find significant overlap of these networks with previously identified dysregulated gene expression modules identified in trisomy 21 fetal brain tissue. We show that harmine leads to partial normalization of key regulators of cortical development, including WNT7A and the transcription factors TBR1, BCL11A, and POU3F2, pointing to a causative role for DYRK1A over-expression in neurodevelopmental effects of human trisomy 21. 4

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“…Social interaction emerges in postnatal life and relies on a morphological scaffold that is structured in early intrauterine developmental stages and depends on intrinsic and extrinsic factors that properly form brain structure to function normally [267-274]. Mutations or biological imbalance disrupts this morphological assembly and produces mild or severe cognitive impairments [275, 276].…”

Section: Neural and Immune Network Underlying Autismmentioning

confidence: 99%

Neuroimmune and Inflammatory Signals in Complex Disorders of the Central Nervous System

Liberman

Trías

Chagas

et al. 2018

Neuroimmunomodulation

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An extensive microglial-astrocyte-monocyte-neuronal cross talk seems to be crucial for normal brain function, development, and recovery. However, under certain conditions neuroinflammatory interactions between brain cells and neuroimmune cells influence disease outcome and brain pathology. Microglial cells express a range of functional states with dynamically pleomorphic profiles from a surveilling status of synaptic transmission to an active player in major events of development such as synaptic elimination, regeneration, and repair. Also, inflammation mediates a series of neurotoxic roles in neuropsychiatric conditions and neurodegenerative diseases. The present review discusses data on the involvement of neuroinflammatory conditions that alter neuroimmune interactions in four different pathologies. In the first section of this review, we discuss the ability of the early developing brain to respond to a focal lesion with a rapid compensatory plasticity of intact axons and the role of microglial activation and proinflammatory cytokines in brain repair. In the second section, we present data of neuroinflammation and neurodegenerative disorders and discuss the role of reactive astrocytes in motor neuron toxicity and the progression of amyotrophic lateral sclerosis. In the third section, we discuss major depressive disorders as the consequence of dysfunctional interactions between neural and immune signals that result in increased peripheral immune responses and increase proinflammatory cytokines. In the last section, we discuss autism spectrum disorders and altered brain circuitries that emerge from abnormal long-term responses of innate inflammatory cytokines and microglial phenotypic dysfunctions.

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Transcriptional and Post-Transcriptional Mechanisms of the Development of Neocortical Lamination

Cited by 39 publications

References 186 publications

Translational derepression of Elavl4 isoforms at their alternative 5′ UTRs determines neuronal development

Translational derepression of Elavl4 isoforms at their alternative 5′ UTRs determines neuronal development

Cerebral organoid proteomics reveals signatures of dysregulated cortical development associated with human trisomy 21

Neuroimmune and Inflammatory Signals in Complex Disorders of the Central Nervous System

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