Paternal imprinting of inversion Uab1 causes homeotic transformations in Drosophila.

Genetics ◽  
1988 ◽  
Vol 118 (1) ◽  
pp. 103-107
Author(s):  
D T Kuhn ◽  
G Packert
Keyword(s):  
Maternal Effect ◽  
Abdominal Segment ◽  
Mutant Phenotype ◽  
Dependent Manner ◽  
Bithorax Complex ◽  
Gain Of Function ◽  
Modifying Genes ◽  
Paternal Transmission ◽  
Genital Disc

Abstract Paternal transmission of the bithorax-complex (BX-C) rearrangement, inversion Uab1, causes a specific dominant gain of function phenotype in most abdominal segments. This represents a case of paternal imprinting since the mutant phenotype will occur only if inversion Uab1 is paternally transmitted. The transformations in males are toward genital arch tissue. For females the transformations are to tissue found on abdominal segment 7 (Ab7) and to structures normally restricted to the genital disc. Ninety-six percent of transformed areas appear on Ab5 and Ab6 in both sexes and on Ab7 in females, coinciding with the Abd-B domain. Four percent of the transformations occurred on Ab1 through Ab4, coinciding with the abd-A domain. The mutant phenotype can be dramatically enhanced by modifying genes such as the posterior BX-C mutant tuh-3. Expressivity is modulated by maternal effect alleles interacting with tuh-3. A region of function within inversion Uab1 appears to be programmed during spermatogenesis to function in a legacy dependent manner during embryogenesis.

Transcription activates repressed domains in theDrosophilabithorax complex

Development ◽  
2002 ◽  
Vol 129 (21) ◽  
pp. 4923-4930 ◽  
Author(s):  
Welcome Bender ◽  
Daniel P. Fitzgerald
Keyword(s):  
Abdominal Segment ◽  
Mutant Phenotype ◽  
P Element ◽  
Bithorax Complex ◽  
Regulatory Regions ◽  
P Elements

A series of mutations have been recovered in the bithorax complex of D. melanogaster that transform the first segment of the abdomen into a copy of the second or third abdominal segment. These dominantUltraabdominal alleles are all associated with P element insertions which are transcribed in the first abdominal segment. The transcripts proceed past the end of the P element for up to 50 kb, extending through the regulatory regions for the second and third abdominal segments. Blocking transcription from the P element promoter reverts the mutant phenotype. Previously identified Ultraabdominal alleles, not associated with P elements, also show abnormal transcription of the same region.

Developmental effects of some newly induced Ultrabithorax alleles of Drosophila

Development ◽  
1982 ◽  
Vol 68 (1) ◽  
pp. 211-234
Author(s):  
Stephen Kerridge ◽  
Gines Morata
Keyword(s):  
Chromosomal Aberrations ◽  
Abdominal Segment ◽  
Larval Period ◽  
Additive Effect ◽  
Bithorax Complex ◽  
Induced Mutations ◽  
Heterozygous Condition ◽  
X Ray ◽  
Developmental Effects ◽  
Blastoderm Stage

Nine X-ray-induced mutations of the bithorax complex (BX-C) have been isolated and characterized. They all show the typical features of the Ultrabithorax mutations. They are homozygous lethal, produce a slight enlargement of the haltere in heterozygous condition and fail to complement the mutations at the bx, bxd and pbx loci. Some of them are associated with chromosomal aberrations in the regions 89E 1-4, where the BX-C lies, while others appear normal cytologically. The effect of six of these mutants in the adult cuticle has been studied, producing mutant marked clones in heterozygous individuals. The clones were generated by X-radiation at two points in development: the blastoderm stage and the second larval period. In all cases mutant clones showed the same phenotype: clones appearing in the dorsal structures transform metathorax and first abdominal segment towards mesothorax. That is the additive effect of bx, bxd and pbx mutations. Clones in the legs, if induced during the larval period, show an effect homologous to that seen in the dorsal structures. However, when produced at blastoderm they show in addition a transformation of the posterior second (mesothoracic) and third (metathoracic) legs into the posterior first (prothoracic) leg. This transformation, named postprothorax (ppx) has been recently described for the alleles Ubx130 and Ubx1 (Morata & Kerridge, 1981) and appears to be general for the Ubxmutations. It is concluded that the realm of action of the Ubx gene is defined by part of the rflesothoracic segment (posterior second leg compartment) and the entire metathoracic and first abdominal segments.

scholarly journals Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner

2018 ◽  
Vol 11 (522) ◽  
pp. eaao1591 ◽  
Author(s):  
Hong Zheng ◽  
Wen-Mei Yu ◽  
Ronald R. Waclaw ◽  
Maria I. Kontaridis ◽  
Benjamin G. Neel ◽  
...  
Keyword(s):  
Tyrosine Phosphatase ◽  
Dependent Manner ◽  
Gain Of Function ◽  
Gene Encoding

scholarly journals Kidney Disease-Associated APOL1 Variants Have Dose-Dependent, Dominant Toxic Gain-of-Function

2020 ◽  
Vol 31 (9) ◽  
pp. 2083-2096 ◽  
Author(s):  
Somenath Datta ◽  
Rama Kataria ◽  
Jia-Yue Zhang ◽  
Savannah Moore ◽  
Kaitlyn Petitpas ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mammalian Cell Culture ◽  
Cellular Stress Response ◽  
Hek293 Cells ◽  
Dependent Manner ◽  
Gain Of Function ◽  
Risk Variants ◽  
Canonical Pathways ◽  
Culture Models ◽  
Dose Dependent

BackgroundTwo coding renal risk variants (RRVs) of the APOL1 gene (G1 and G2) are associated with large increases in CKD rates among populations of recent African descent, but the underlying molecular mechanisms are unknown. Mammalian cell culture models are widely used to study cytotoxicity of RRVs, but results have been contradictory. It remains unclear whether cytotoxicity is RRV-dependent or driven solely by variant-independent overexpression. It is also unknown whether expression of the reference APOL1 allele, the wild-type G0, could prevent cytotoxicity of RRVs.MethodsWe generated tetracycline-inducible APOL1 expression in human embryonic kidney HEK293 cells and examined the effects of increased expression of APOL1 (G0, G1, G2, G0G0, G0G1, or G0G2) on known cytotoxicity phenotypes, including reduced viability, increased swelling, potassium loss, aberrant protein phosphorylation, and dysregulated energy metabolism. Furthermore, whole-genome transcriptome analysis examined deregulated canonical pathways.ResultsAt moderate expression, RRVs but not G0 caused cytotoxicity in a dose-dependent manner that coexpression of G0 did not reduce. RRVs also have dominant effects on canonical pathways relevant for the cellular stress response.ConclusionsIn HEK293 cells, RRVs exhibit a dominant toxic gain-of-function phenotype that worsens with increasing expression. These observations suggest that high steady-state levels of RRVs may underlie cellular injury in APOL1 nephropathy, and that interventions that reduce RRV expression in kidney compartments may mitigate APOL1 nephropathy.

The Physiology of Prothrombin Gene Expression Integrates RNA Polyadenylation and Splicing in a Novel Regulatable 3′ RNP-Complex.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1601-1601
Author(s):  
Sven Danckwardt ◽  
Marc Gentzel ◽  
Niels H. Gehring ◽  
Isabelle Kaufmann ◽  
Gabriele Neu-Yilik ◽  
...  
Keyword(s):  
Gene Expression ◽  
Splicing Factors ◽  
Upstream Sequence ◽  
Dependent Manner ◽  
Flanking Sequence ◽  
Gain Of Function ◽  
Sequence Element ◽  
Functional Link ◽  
Rnp Complex ◽  
Prothrombin Gene

Abstract The functional analysis of the common prothrombin (F2) 20210*A allele has recently revealed gain-of-function of 3′end processing as a novel genetic mechanism predisposing to human disease. The general susceptibility of the F2 mRNA for gain-of-function is further exemplified by F2 20209*T and F2 20221*T, and can be explained by an unusual architecture of non-canonical 3′end formation sequence elements: Specifically, the F2 3′ untranslated region (3′UTR) contains a stimulatory upstream sequence element (USE) that compensates for the weak functional activities of the cleavage site and the downstream U-rich element in the F2 3′ flanking sequence. We now show that the F2 USE promotes 3′end formation in a position- and sequence-dependent manner, stimulating the step of mRNA polyadenylation rather than cleavage, and identify specific proteins that interact with the USE. Unexpectedly, the USE RNP includes splicing factors, components of the 3′end processing machinery and AU-rich sequence element-binding proteins (ARE-BP). We demonstrate that the splicing factors U2AF35 and U2AF65, hnRNPI/PTB, PSF/SFPQ and p54nrb/NonO promote 3′end formation via the USE contained in the 3′UTR uncovering a novel and more general functional link between these splicing factors and mRNA 3′ end formation. We propose a model of USE-directed 3′ end processing that involves a novel mRNP that integrates different nuclear pre-mRNA processing steps. Furthermore, the involvement of ARE-BP in this mRNP reveals an intriguing potential for a post-transcriptional regulation of prothrombin gene expression through external stimuli. Our data thus implicate USE-dependent RNP-complex formation in the regulated physiology of prothrombin gene expression specifically and in hemostasis (and other thrombin-dependent processes) more generally.

scholarly journals A Drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanism

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Elliot Imler ◽  
Jin Sang Pyon ◽  
Selina Kindelay ◽  
Meaghan Torvund ◽  
Yong-quan Zhang ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Gene Dosage ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Dependent Manner ◽  
Membrane Structures ◽  
Gain Of Function ◽  
Function Mechanism ◽  
Ubiquitinated Proteins ◽  
Drosophila Model

The autosomal dominant neuronal ceroid lipofuscinoses (NCL) CLN4 is caused by mutations in the synaptic vesicle (SV) protein CSPα. We developed animal models of CLN4 by expressing CLN4 mutant human CSPα (hCSPα) in Drosophila neurons. Similar to patients, CLN4 mutations induced excessive oligomerization of hCSPα and premature lethality in a dose-dependent manner. Instead of being localized to SVs, most CLN4 mutant hCSPα accumulated abnormally, and co-localized with ubiquitinated proteins and the prelysosomal markers HRS and LAMP1. Ultrastructural examination revealed frequent abnormal membrane structures in axons and neuronal somata. The lethality, oligomerization and prelysosomal accumulation induced by CLN4 mutations was attenuated by reducing endogenous wild type (WT) dCSP levels and enhanced by increasing WT levels. Furthermore, reducing the gene dosage of Hsc70 also attenuated CLN4 phenotypes. Taken together, we suggest that CLN4 alleles resemble dominant hypermorphic gain of function mutations that drive excessive oligomerization and impair membrane trafficking.

scholarly journals CircSETD3 (Hsa_circ_0000567) Suppresses Hepatoblastoma Pathogenesis via Targeting the miR-423-3p/Bcl-2-Interacting Mediator of Cell Death Axis

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin Li ◽  
Haojie Wang ◽  
Zhijie Liu ◽  
Alimujiang Abudureyimu
Keyword(s):  
Regulatory Mechanism ◽  
Epithelial Mesenchymal Transition ◽  
Circular Rna ◽  
Cell Counting ◽  
Dependent Manner ◽  
Mice Model ◽  
Gain Of Function ◽  
Mesenchymal Transition

Background: Up until now, the role of circSETD3 (Has_circ_0000567) in regulating cancer development has been reported in several tumors, but the role and regulatory mechanism of circSETD3 in hepatoblastoma (HB) remain unclear.Methods: The qPCR and western blotting were used to determine the mRNA and protein levels in the present study. Stability of circular RNA was detected by RNA digested experiments. The gain-of-function and rescue experiments were used to explore the function and mechanism of circSETD3 in HB. Cell counting kit-8, colony formation, transwell assay, and xenograft mice model were used to detect effects and regulatory mechanism of circSETD3/miR-423-3p/Bim axis on cell aggressive phenotype in vitro and in vivo.Results: Here, we identified that circSETD3 downregulated in both HB clinical tissues and cell lines, compared to that of normal tissues and cells. Further gain-of-function experiments validated that circSETD3 overexpression inhibited cell proliferation, viability, migration, epithelial-mesenchymal transition (EMT) and tumorigenesis, and induced cell apoptosis in HB cells. Next, we validated that miR-423-3p targeted both circSETD3 and 3′ untranslated region (3′UTR) of Bim, and circSETD3 positively regulated Bim in HB cells through sponging miR-423-3p in a competing endogenous RNA (ceRNA)-dependent manner. Furthermore, through conducting reversal experiments, we evidenced that the inhibiting effects of circSETD3 overexpression on HB development were abrogated by upregulating miR-423-3p and downregulating Bim.Conclusion: Taken together, we evidenced that circSETD3 sponged miR-423-3p to upregulate Bim, resulting in the inhibition of HB development.

scholarly journals Gain-of-function mutations in the UNC-2/CaV2α channel lead to hyperactivity and excitation-dominant synaptic transmission in Caenorhabditis elegans

2019 ◽  
Author(s):  
Yung-Chi Huang ◽  
Jennifer K. Pirri ◽  
Diego Rayes ◽  
Shangbang Gao ◽  
Ben Mulcahy ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Familial Hemiplegic Migraine ◽  
Calcium Currents ◽  
Dependent Manner ◽  
Cellular Mechanisms ◽  
Gain Of Function ◽  
Motor Behaviors ◽  
Insight Into ◽  
Α1 Subunit

AbstractMutations in pre-synaptic voltage gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the Caenorhabditis elegans CaV2 channel α1 subunit, UNC-2, which leads to increased calcium currents. unc-2(gf) mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the unc-2 gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of unc-2(gf) mutants unc-2(gf) mutants display increased cholinergic- and decreased GABAergic-transmission. Moreover, we reveal that and increased cholinergic transmission in unc-2(gf) mutants leads to reduction of GABA synapses in a TAX-6/calcineurin dependent manner. Our studies provide mechanistic insight into how CaV2 gain-of-function mutations disrupt excitation-inhibition balance in the nervous system.

scholarly journals Gain-of-function genetic screen of the kinome reveals BRSK2 as an inhibitor of the NRF2 transcription factor

2019 ◽  
Author(s):  
Tigist Y Tamir ◽  
Brittany M Bowman ◽  
Megan J Agajanian ◽  
Dennis Goldfarb ◽  
Travis P Schrank ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Synthesis ◽  
Human Cancer ◽  
Genetic Screen ◽  
Mtor Signaling ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Gain Of Function ◽  
Protein Levels ◽  
Nrf2 Protein

AbstractNFE2L2/NRF2 is a transcription factor and master regulator of cellular antioxidant response. Aberrantly high NRF2-dependent transcription is recurrent in human cancer, and conversely NRF2 protein levels as well as activity is diminished with age and in neurodegenerative disorders. Though NRF2 activating drugs are clinically beneficial, NRF2 inhibitors do not yet exist. Here we used a gain-of-function genetic screen of the kinome to identify new druggable regulators of NRF2 signaling. We found that the understudied protein kinase Brain Specific Kinase 2 (BRSK2) and the related BRSK1 kinases suppress NRF2-dependent transcription and NRF2 protein levels in an activity-dependent manner. Integrated phosphoproteomics and RNAseq studies revealed that BRSK2 drives AMPK activation and suppresses mTOR signaling. As a result, BRSK2 kinase activation suppressed ribosome-RNA complexes, global protein synthesis, and NRF2 protein levels. Collectively, our data establish the catalytically active BRSK2 kinase as a negative regulator of NRF2 via the AMPK/mTOR signaling. This signaling axis may prove useful for therapeutically targeting NRF2 in human diseases.Summary StatementBRSK2 suppresses NRF2 signaling by inhibiting protein synthesis through mTOR downregulation.

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