Evolutionary expansion and complexification of the primate cerebral cortex are largely linked to the emergence of the outer subventricular zone (OSVZ), a uniquely structured germinal zone that ...generates the expanded primate supragranular layers. The primate OSVZ departs from rodent germinal zones in that it includes a higher diversity of precursor types, inter-related in bidirectional non-hierarchical lineages. In addition, primate-specific regulatory mechanisms are operating in primate cortical precursors via the occurrence of novel miRNAs. Here, we propose that the origin and evolutionary importance of the OSVZ is related to genetic changes in multiple regulatory loops and that cell-cycle regulation is a favored target for evolutionary adaptation of the cortex.
In this comprehensive overview of the molecular and cellular determinants governing OSVZ progenitor performance in primates, Dehay, Kennedy, and Kosik argue that cell-cycle regulation is an evolutionary determinant responsible for a primate-specific molecular and cellular logic driving primate cortical complexification
The neuronal microRNA system Kosik, Kenneth S
Nature reviews. Neuroscience,
12/2006, Letnik:
7, Številka:
12
Journal Article
Recenzirano
A class of small, non-coding transcripts called microRNAs (miRNAs) that provide a crucial and pervasive layer of post-transcriptional gene regulation has recently emerged and become the focus of ...intense research. miRNAs are abundant in the nervous system, where they have key roles in development and are likely to be important mediators of plasticity. A highly conserved pathway of miRNA biogenesis is closely linked to the transport and translatability of mRNAs in neurons. Although there are nearly 500 known human miRNA sequences, each of only approximately 21 nucleotides, which bind to multiple mRNA targets, the accurate prediction of miRNA targets seems to lie just beyond our grasp. Nevertheless, the identification of such targets promises to provide new insights into many facets of neuronal function.
Large families with autosomal dominant mutations leading to Alzheimer's disease and related conditions can reveal putative protective gene variants; however, no systematic search strategy exists to ...find these genes. Described here are the unique demographic circumstances and genetic setting in which the discovery of protective variants is likely. The identification of these genes may reveal pathways with therapeutic implications. This article is protected by copyright. All rights reserved.
MicroRNA dysregulation is observed in different types of cancer. MiR-21 up-regulation has been reported for the majority of cancers profiled to date; however, knowledge is limited on the mechanism of ...action of miR-21, including identification of functionally important targets that contribute to its proproliferative and antiapoptotic actions. In this study, we show for the first time that miR-21 targets multiple important components of the p53, transforming growth factor-beta (TGF-beta), and mitochondrial apoptosis tumor-suppressive pathways. Down-regulation of miR-21 in glioblastoma cells leads to derepression of these pathways, causing repression of growth, increased apoptosis, and cell cycle arrest. These phenotypes are dependent on two of the miR-21 targets validated in this study, HNRPK and TAp63. These findings establish miR-21 as an important oncogene that targets a network of p53, TGF-beta, and mitochondrial apoptosis tumor suppressor genes in glioblastoma cells.
Long non-coding RNAs (lncRNAs) are a diverse and poorly conserved category of transcripts that have expanded greatly in primates, particularly in the brain. We identified an lncRNA, which has ...acquired 16 microRNA response elements for miR-143-3p in the Catarrhini branch of primates. This lncRNA, termed LncND (neurodevelopment), is expressed in neural progenitor cells and then declines in neurons. Binding and release of miR-143-3p by LncND control the expression of Notch receptors. LncND expression is enriched in radial glia cells (RGCs) in the ventricular and subventricular zones of developing human brain. Downregulation in neuroblastoma cells reduced cell proliferation and induced neuronal differentiation, an effect phenocopied by miR-143-3p overexpression. Gain of function of LncND in developing mouse cortex led to an expansion of PAX6+ RGCs. These findings support a role for LncND in miRNA-mediated regulation of Notch signaling within the neural progenitor pool in primates that may have contributed to the expansion of cerebral cortex.
•Identification of LncND with a Catarrhine insertion of 16 MREs for miR-143-3p•LncND regulates expression of Notch genes by sequestering miR-143-3p•High expression of LncND in radial glia cells in human VZ and OSVZ•LncND appears to be involved in the expansion of radial glia cells in primates
Rani et al. demonstrate the function of a primate lncRNA, designated LncND, as a miRNA reservoir regulating the expression of Notch-1 and Notch-2 by sequestering miR-143-3p. They provide evidence for the involvement of LncND in primate brain expansion.
Most mammalian dendrites have surprisingly few copy numbers of mRNAs relative to the large number of synapses and consequently, at any given moment, the majority of synapses do not have a repertoire ...of mRNAs within their immediate locale capable of initiating translation-dependent plasticity. The dimensions of the translationally serviceable locale around synapses have boundary parameters that can be estimated. When a synapse receives an input beyond that boundary, the requisite mRNAs for local translation and plasticity may not be there. How a complex dendritic arbor optimizes this paucity of mRNAs opens several functional considerations that are related to the dynamic range of dendritic plasticity, sparse coding, and modifications of firing rates. RNA localization in dendrites may instantiate a neuron’s history and establishes a bias toward inputs that synapse on RNA-laden synaptic clusters. Low copy numbers create an element of stochasticity to the induction of translation-dependent plasticity that allows the dendrite opportunities to respond to novel and unexpected inputs.
Kosik estimates copy numbers of mRNAs in pyramidal cell dendrites and finds surprisingly few relative to the numbers of synapses. Therefore, synapses fall along a distribution of translational competence depending upon their access to those mRNAs necessary for plasticity.
Tau and the hard problem faceoff Kosik, Kenneth S.
Cytoskeleton,
January 2024, 2024-01-00, 20240101, Letnik:
81, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Tau has attracted the attention of fundamental cell biologists for its control over microtubules and Alzheimer biologists for its tendency to form pathological inclusions. While an extensive and ...insightful literature exists on the tauopathies and vulnerable cell populations, we should acknowledge that a core problem remains—how the individually variable experience of dementia is embodied, how it is felt.
Neural stem cells have been adopted to model a wide range of neuropsychiatric conditions in vitro. However, how well such models correspond to in vivo brain has not been evaluated in an unbiased, ...comprehensive manner. We used transcriptomic analyses to compare in vitro systems to developing human fetal brain and observed strong conservation of in vivo gene expression and network architecture in differentiating primary human neural progenitor cells (phNPCs). Conserved modules are enriched in genes associated with ASD, supporting the utility of phNPCs for studying neuropsychiatric disease. We also developed and validated a machine learning approach called CoNTExT that identifies the developmental maturity and regional identity of in vitro models. We observed strong differences between in vitro models, including hiPSC-derived neural progenitors from multiple laboratories. This work provides a systems biology framework for evaluating in vitro systems and supports their value in studying the molecular mechanisms of human neurodevelopmental disease.
•Quantitative framework permits comparisons of in vitro models to in vivo brain•phNPCs recapitulate cortical development up to late mid-fetal periods•In vivo cortical gene networks implicated in ASD are preserved in phNPCs•Highlights key differences between widely used stem cell models and in vivo brain
Human neural stem cells have been adopted to model a wide range of neuropsychiatric conditions in vitro. Here, Stein et al. develop a bioinformatic framework to quantitatively evaluate their ability to model in vivo cortical development and their translational potential.
MicroRNAs (miRNAs) are posttranscriptional modulators of gene expression and play an important role in many developmental processes. We report here that expression of microRNA-145 (miR-145) is low in ...self-renewing human embryonic stem cells (hESCs) but highly upregulated during differentiation. We identify the pluripotency factors OCT4, SOX2, and KLF4 as direct targets of miR-145 and show that endogenous miR-145 represses the 3′ untranslated regions of OCT4, SOX2, and KLF4. Increased miR-145 expression inhibits hESC self-renewal, represses expression of pluripotency genes, and induces lineage-restricted differentiation. Loss of miR-145 impairs differentiation and elevates OCT4, SOX2, and KLF4. Furthermore, we find that the miR-145 promoter is bound and repressed by OCT4 in hESCs. This work reveals a direct link between the core reprogramming factors and miR-145 and uncovers a double-negative feedback loop involving OCT4, SOX2, KLF4, and miR-145.
Under defined differentiation conditions, human embryonic stem cells (hESCs) can be directed toward a mesendoderm (ME) or neuroectoderm (NE) fate, the first decision during hESC differentiation. ...Coupled with lineage-specific G1 lengthening, a divergent ciliation pattern emerged within the first 24 hr of induced lineage specification, and these changes heralded a neuroectoderm decision before any neural precursor markers were expressed. By day 2, increased ciliation in NE precursors induced autophagy that resulted in the inactivation of Nrf2 and thereby relieved transcriptional activation of OCT4 and NANOG. Nrf2 binds directly to upstream regions of these pluripotency genes to promote their expression and repress NE derivation. Nrf2 suppression was sufficient to rescue poorly neurogenic iPSC lines. Only after these events had been initiated did neural precursor markers get expressed at day 4. Thus, we have identified a primary cilium-autophagy-Nrf2 (PAN) control axis coupled to cell-cycle progression that directs hESCs toward NE.
Display omitted
•NE-specific G1 lengthening initiates NE derivation through primary cilia•Increased ciliogenesis activates autophagy and presages NE differentiation•NE precursor-specific autophagy inactivates Nrf2•Nrf2 suppresses NE fate by directly controlling OCT4 and NANOG expression
A primary cilium-autophagy-Nrf2 axis couples with the cell-cycle progression and regulates the inactivation of Oct4 and Nanog, therefore serving as the earliest cascade of triggering events to initiate stem cell differentiation into neuroectoderm.
PDF
