Abstract：
:Identifying modifiers of dosage-sensitive genes involved in neurodegenerative disorders is imperative to discover novel genetic risk factors and potential therapeutic entry points. In this study, we focus on Ataxin-1 (ATXN1), a dosage-sensitive gene involved in the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1). While the precise maintenance of ATXN1 levels is essential to prevent disease, the mechanisms that regulate ATXN1 expression remain largely unknown. We demonstrate that ATXN1's unusually long 5' untranslated region (5' UTR) negatively regulates its expression via posttranscriptional mechanisms. Based on recent reports that microRNAs (miRNAs) can interact with both 3' and 5' UTRs to regulate their target genes, we identify miR760 as a negative regulator that binds to a conserved site in ATXN1's 5' UTR to induce RNA degradation and translational inhibition. We found that delivery of Adeno-associated virus (AAV)-expressing miR760 in the cerebellum reduces ATXN1 levels in vivo and mitigates motor coordination deficits in a mouse model of SCA1. These findings provide new insights into the regulation of ATXN1 levels, present additional evidence for miRNA-mediated gene regulation via 5' UTR binding, and raise the possibility that noncoding mutations in the ATXN1 locus may act as risk factors for yet to be discovered progressive ataxias.
journal_name
Genes Devjournal_title
Genes & developmentauthors
Nitschke L,Tewari A,Coffin SL,Xhako E,Pang K,Gennarino VA,Johnson JL,Blanco FA,Liu Z,Zoghbi HYdoi
10.1101/gad.339317.120subject
Has Abstractpub_date
2020-09-01 00:00:00pages
1147-1160issue
17-18eissn
0890-9369issn
1549-5477pii
gad.339317.120journal_volume
34pub_type
杂志文章abstract：:The mammary tumor-associated proto-oncogene Wnt-1/int-1 encodes a secreted protein implicated in the regulation of neural development in vertebrates and segmental pattern in Drosophila. Using a PCR-based strategy, we isolated cDNAs encoding six novel, related proteins that are expressed in fetal mice. Predicted protei...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.4.12b.2319
更新日期：1990-12-01 00:00:00
abstract：:Deregulated expression of the c-myc proto-oncogene can lead to apoptosis under certain physiological conditions. By introducing a conditionally active Myc allele into primary embryo fibroblasts null for p53, and into fibroblasts without endogenous p53 expression but ectopically expressing a temperature-sensitive p53 a...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.8.23.2817
更新日期：1994-12-01 00:00:00
abstract：:Somatic cell clones often fail at a developmental stage coincident with commencement of differentiation. The transcription factor Oct4 is expressed during cleavage stages and is essential for the differentiation of the blastocyst. Oct4 expression becomes restricted to the inner cell mass and epiblast. After gastrulati...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.966002
更新日期：2002-05-15 00:00:00
abstract：:Gut homeostasis is controlled by both immune and developmental mechanisms, and its disruption can lead to inflammatory disorders or cancerous lesions of the intestine. While the impact of bacteria on the mucosal immune system is beginning to be precisely understood, little is known about the effects of bacteria on gut...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.1827009
更新日期：2009-10-01 00:00:00
abstract：:Dorsal mesoderm induction in arthropods and ventral mesoderm induction in vertebrates are closely related processes that involve signals of the BMP family. In Drosophila, induction of visceral mesoderm, dorsal muscles, and the heart by Dpp is, at least in part, effected through the transcriptional activation and funct...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.12.15.2354
更新日期：1998-08-01 00:00:00
abstract：:Medulloblastomas are among the most common malignancies in childhood, and they are associated with substantial mortality and morbidity. The molecular pathogenesis as well as the ontogeny of these neoplasms is still poorly understood. We have generated a mouse model for medulloblastoma by Cre-LoxP-mediated inactivation...
journal_title：Genes & development
pub_type： 杂志文章
doi：
更新日期：2000-04-15 00:00:00
abstract：:Bistability in developmental pathways refers to the generation of binary outputs from graded or noisy inputs. Signaling thresholds are critical for bistability. Specification of the left/right (LR) axis in vertebrate embryos involves bistable expression of transforming growth factor beta (TGFbeta) member NODAL in the ...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.1682108
更新日期：2008-11-01 00:00:00
abstract：:The liver regenerates upon partial hepatectomy (PH) as terminally differentiated hepatocytes undergo a tremendous proliferative process. CREM gene expression is powerfully induced during liver regeneration. We show that cell proliferation is significantly reduced upon PH in CREM-/- mice. There is a reduction in DNA sy...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.12.23.3639
更新日期：1998-12-01 00:00:00
abstract：:The gene for an essential protein subunit of nuclear RNase P from Saccharomyces cerevisiae has been cloned. The gene for this protein, RPP1, was identified by virtue of its homology with a human scleroderma autoimmune antigen, Rpp30, which copurifies with human RNase P. Epitope-tagged Rpp1 can be found in association ...
journal_title：Genes & development
pub_type： 更正并重新发布的文章,杂志文章
doi：10.1101/gad.11.21.2926
更新日期：1997-11-01 00:00:00
abstract：:The yeast SAGA (Spt-Ada-Gcn5-acetyltransferase) coactivator complex exerts functions in gene expression, including activator interaction, histone acetylation, histone deubiquitination, mRNA export, chromatin recognition, and regulation of the basal transcription machinery. These diverse functions involve distinct modu...
journal_title：Genes & development
pub_type： 杂志文章,评审
doi：10.1101/gad.184705.111
更新日期：2012-03-15 00:00:00
abstract：:The nonsense-mediated mRNA decay (NMD) pathway selectively degrades mRNAs harboring premature termination codons (PTCs). Seven genes (smg-1-7, for suppressor with morphological effect on genitalia) that are essential for NMD were originally identified in the nematode Caenorhabditis elegans, and orthologs of these gene...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.417707
更新日期：2007-05-01 00:00:00
abstract：:Proliferation of pancreatic islet beta cells is an important mechanism for self-renewal and for adaptive islet expansion. Increased expression of the Ink4a/Arf locus, which encodes the cyclin-dependent kinase inhibitor p16(INK4a) and tumor suppressor p19(Arf), limits beta-cell regeneration in aging mice, but the basis...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.1742509
更新日期：2009-04-15 00:00:00
abstract：:Growth of numerous cancer types is believed to be driven by a subpopulation of poorly differentiated cells, often referred to as cancer stem cells (CSCs), that have the capacity for self-renewal, tumor initiation, and generation of nontumorigenic progeny. Despite their potentially key role in tumor establishment and m...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.188292.112
更新日期：2012-09-01 00:00:00
abstract：:Deletions and other chromosomal rearrangements can be generated by recombination between repeated sequences. It has been shown in a number of systems that the probability of exchange or gene conversion decreases with increasing distance between repeats. This paper examines the question of how repeats find each other, ...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.2.12b.1800
更新日期：1988-12-01 00:00:00
abstract：:Atypical teratoid rhabdoid tumors (ATRTs) are challenging pediatric brain cancers that are predominantly associated with inactivation of the gene SMARCB1, a conserved subunit of the chromatin remodeling BAF complex, which has known contributions to developmental processes. To identify potential interactions between SM...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.339978.120
更新日期：2020-10-01 00:00:00
abstract：:The Rho family of small GTPases are critical elements involved in the regulation of signal transduction cascades from extracellular stimuli to the cell nucleus, including the JNK/SAPK signaling pathway, the c-fos serum response factor, and the p70 S6 kinase. Here we report a novel signaling pathway activated by the Rh...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.11.4.463
更新日期：1997-02-15 00:00:00
abstract：:A powerful enhancer has been mapped to an 18-bp DNA segment located 11 kb 5' to the human epsilon-globin gene within the dominant control or locus-activating region. This enhancer is inducible in K562 human erythroleukemia cells, increasing linked gamma-globin promoter/luciferase gene expression to 170-fold over an en...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.4.6.993
更新日期：1990-06-01 00:00:00
abstract：:Abcission, the natural shedding of leaves, flowers and fruits, is a fundamental component of plant development. Abscission is a highly regulated process that occurs at distinct zones of cells that undergo enlargement and subsequent separation. Although some components of abscission, including accumulation of the hormo...
journal_title：Genes & development
pub_type： 杂志文章
doi：
更新日期：2000-01-01 00:00:00
abstract：:Wingless (Wg) is an important signaling molecule in the development of Drosophila, but little is known about its signal transduction pathway. Genetic evidence indicates that another segment polarity gene, dishevelled (dsh) is required for Wg signaling. We have recently developed a cell culture system for Wg protein ac...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.9.9.1087
更新日期：1995-05-01 00:00:00
abstract：:Cellular morphology is an essential determinant of cellular function in all kingdoms of life, yet little is known about how cell shape is controlled. Here we describe a molecular program that controls the early morphology of neurons through a metazoan-specific zinc finger protein, Unkempt. Depletion of Unkempt in mous...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.258483.115
更新日期：2015-03-01 00:00:00
abstract：:The SNF1 protein kinase is broadly conserved in eukaryotes and has been implicated in responses to environmental and nutritional stress. In yeast, the SNF1 kinase has a central role in the response to glucose starvation. SNF1 is associated with its activating subunit, SNF4, and other proteins in complexes. Using the t...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.10.24.3105
更新日期：1996-12-15 00:00:00
abstract：:High-fidelity chromosome transmission is fundamental in controlling the quality of the cell division cycle. The spindle pole-to-pole distance remains constant from metaphase to anaphase A. We show that fission yeast sister centromere-connecting proteins, Mis6 and Mis12, are required for correct spindle morphogenesis, ...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.13.13.1664
更新日期：1999-07-01 00:00:00
abstract：:The generation of neurons by progenitor cells involves the tight coordination of multiple cellular activities, including cell cycle exit, initiation of neuronal differentiation, and cell migration. The mechanisms that integrate these different events into a coherent developmental program are not well understood. Here ...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.377106
更新日期：2006-06-01 00:00:00
abstract：:Changes in the pattern of gene expression play an important role in allowing cancer cells to acquire their hallmark characteristics, while genomic instability enables cells to acquire genetic alterations that promote oncogenesis. Chromatin plays central roles in both transcriptional regulation and the maintenance of g...
journal_title：Genes & development
pub_type： 杂志文章,评审
doi：10.1101/gad.255182.114
更新日期：2015-02-01 00:00:00
abstract：:Cell growth and differentiation are usually antagonistic. Proteins of the basic helix-loop-helix (bHLH) family bind DNA and play important roles in the differentiation of specific cell types. Id proteins heterodimerize with bHLH transcription factors, blocking their activation of lineage-specific gene expression and t...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.8.11.1270
更新日期：1994-06-01 00:00:00
abstract：:Telomerase is a ribonucleoprotein enzyme that adds telomeric repeats to chromosomes, maintaining telomere length and stabilizing chromosome ends. In vitro, telomerase from the ciliate Tetrahymena elongates single-stranded, guanosine-rich DNA primers by adding repeats of the Tetrahymena telomeric sequence, dT2G4. We ha...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.7.7b.1364
更新日期：1993-07-01 00:00:00
abstract：:Disruption of the balanced modulation of reversible tyrosine phosphorylation has been implicated in the etiology of various human cancers, including breast cancer. Protein Tyrosine Phosphatase N23 (PTPN23) resides in chromosomal region 3p21.3, which is hemizygously or homozygously lost in some breast cancer patients. ...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.304261.117
更新日期：2017-10-01 00:00:00
abstract：:We describe three strains of transgenic mice derived by embryo microinjection of DNA consisting of a long terminal repeat (LTR) of Moloney murine sarcoma virus (Mo-MSV) linked to the murine c-mos coding sequences. Southern analysis of the genomic DNA of these strains suggested that in each case the transgene had integ...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.1.10.1327
更新日期：1987-12-01 00:00:00
abstract：:The activity of the polyoma virus (PyV) origin of DNA replication was used as a sensitive assay for enhancer function in one- and two-cell mouse embryos by injecting embryos with plasmid DNA containing different PyV ori configurations, allowing them to continue development in vitro, and then measuring plasmid DNA repl...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.2.9.1115
更新日期：1988-09-01 00:00:00
abstract：:We report on the function of the human ortholog of Saccharomyces cerevisiae Rif1 (Rap1-interacting factor 1). Yeast Rif1 associates with telomeres and regulates their length. In contrast, human Rif1 did not accumulate at functional telomeres, but localized to dysfunctional telomeres and to telomeric DNA clusters in AL...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.1216004
更新日期：2004-09-01 00:00:00
