The Hox gene Antennapedia regulates wing development through 20-hydroxyecdysone in insect

A long-standing view in the field of evo-devo is that insect forewings develop without any Hox gene input. The Hox gene Antennapedia (Antp), despite being expressed in the thoracic segments of insects, has no effect on wing development. This view has been obtained from studies in two main model species, Drosophila and Tribolium. Here, we show that partial loss of function of Antp resulted in reduced and malformed adult wings in Bombyx, Drosophila, and Tribolium. Antp mediates wing growth in Bombyx by directly regulating the ecdysteriod biosynthesis enzyme gene (shade) in the wing tissue, which leads to local production of the growth hormone 20E. In turn, 20E signaling also up-regulates Antp. Additional targets of Antp are wing cuticular protein genes CPG24, CPH28, and CPG9, essential for wing development. We propose, thus, that insect wing development occurs in an Antp-dependent manner.

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Roles for RNA export factor, Nxt1, in ensuring muscle integrity and normal RNA expression in Drosophila

G3 Genes|Genome|Genetics ◽

10.1093/g3journal/jkaa046 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Kevin van der Graaf ◽

Katia Jindrich ◽

Robert Mitchell ◽

Helen White-Cooper

Keyword(s):

Mrna Export ◽

Rna Stability ◽

Muscle Degeneration ◽

Loss Of Function ◽

Cellular Functions ◽

Partial Loss ◽

Export Pathway ◽

Pathway Gene ◽

Rna Export

Abstract The mRNA export pathway is responsible for the transport of mRNAs from the nucleus to the cytoplasm, and thus is essential for protein production and normal cellular functions. A partial loss of function allele of the mRNA export factor Nxt1 in Drosophila shows reduced viability and sterility. A previous study has shown that the male fertility defect is due to a defect in transcription and RNA stability, indicating the potential for this pathway to be implicated in processes beyond the known mRNA transport function. Here we investigate the reduced viability of Nxt1 partial loss of function mutants, and describe a defect in growth and maintenance of the larval muscles, leading to muscle degeneration. RNA-seq revealed reduced expression of a set of mRNAs, particularly from genes with long introns in Nxt1 mutant carcass. We detected differential expression of circRNA, and significantly fewer distinct circRNAs expressed in the mutants. Despite the widespread defects in gene expression, muscle degeneration was rescued by increased expression of the costamere component tn (abba) in muscles. This is the first report of a role for the RNA export pathway gene Nxt1 in the maintenance of muscle integrity. Our data also links the mRNA export pathway to a specific role in the expression of mRNA and circRNA from common precursor genes, in vivo.

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A Cuticle Collagen Encoded by the lon-3 Gene May Be a Target of TGF-β Signaling in Determining Caenorhabditis elegans Body Shape

Genetics ◽

10.1093/genetics/162.4.1631 ◽

2002 ◽

Vol 162 (4) ◽

pp. 1631-1639

Author(s):

Yo Suzuki ◽

Gail A Morris ◽

Min Han ◽

William B Wood

Keyword(s):

Caenorhabditis Elegans ◽

Body Shape ◽

Small Body ◽

Dependent Manner ◽

Loss Of Function ◽

Cellular Mechanisms ◽

C Elegans ◽

Gene Expression Analyses ◽

Dose Dependent

Abstract The signaling pathway initiated by the TGF-β family member DBL-1 in Caenorhabditis elegans controls body shape in a dose-dependent manner. Loss-of-function (lf) mutations in the dbl-1 gene cause a short, small body (Sma phenotype), whereas overexpression of dbl-1 causes a long body (Lon phenotype). To understand the cellular mechanisms underlying these phenotypes, we have isolated suppressors of the Sma phenotype resulting from a dbl-1(lf) mutation. Two of these suppressors are mutations in the lon-3 gene, of which four additional alleles are known. We show that lon-3 encodes a collagen that is a component of the C. elegans cuticle. Genetic and reporter-gene expression analyses suggest that lon-3 is involved in determination of body shape and is post-transcriptionally regulated by the dbl-1 pathway. These results support the possibility that TGF-β signaling controls C. elegans body shape by regulating cuticle composition.

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The Parkinson’s Disease-Associated Protein DJ-1 Protects Dictyostelium Cells from AMPK-Dependent Outcomes of Oxidative Stress

Cells ◽

10.3390/cells10081874 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1874

Author(s):

Suwei Chen ◽

Sarah J. Annesley ◽

Rasha A. F. Jasim ◽

Paul R. Fisher

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Mitochondrial Respiration ◽

Cysteine Residue ◽

Reduced Form ◽

Dependent Manner ◽

Loss Of Function ◽

Cellular Pathology

Mitochondrial dysfunction has been implicated in the pathology of Parkinson’s disease (PD). In Dictyostelium discoideum, strains with mitochondrial dysfunction present consistent, AMPK-dependent phenotypes. This provides an opportunity to investigate if the loss of function of specific PD-associated genes produces cellular pathology by causing mitochondrial dysfunction with AMPK-mediated consequences. DJ-1 is a PD-associated, cytosolic protein with a conserved oxidizable cysteine residue that is important for the protein’s ability to protect cells from the pathological consequences of oxidative stress. Dictyostelium DJ-1 (encoded by the gene deeJ) is located in the cytosol from where it indirectly inhibits mitochondrial respiration and also exerts a positive, nonmitochondrial role in endocytosis (particularly phagocytosis). Its loss in unstressed cells impairs endocytosis and causes correspondingly slower growth, while also stimulating mitochondrial respiration. We report here that oxidative stress in Dictyostelium cells inhibits mitochondrial respiration and impairs phagocytosis in an AMPK-dependent manner. This adds to the separate impairment of phagocytosis caused by DJ-1 knockdown. Oxidative stress also combines with DJ-1 loss in an AMPK-dependent manner to impair or exacerbate defects in phototaxis, morphogenesis and growth. It thereby phenocopies mitochondrial dysfunction. These results support a model in which the oxidized but not the reduced form of DJ-1 inhibits AMPK in the cytosol, thereby protecting cells from the adverse consequences of oxidative stress, mitochondrial dysfunction and the resulting AMPK hyperactivity.

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H3K27 modifiers regulate lifespan in C. elegans in a context-dependent manner

BMC Biology ◽

10.1186/s12915-021-00984-8 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Abigail R. R. Guillermo ◽

Karolina Chocian ◽

Gavriil Gavriilidis ◽

Julien Vandamme ◽

Anna Elisabetta Salcini ◽

...

Keyword(s):

Lifespan Extension ◽

Dependent Manner ◽

Loss Of Function ◽

Animal Cells ◽

C Elegans ◽

Specific Effects ◽

Aberrant Gene Expression ◽

Lysine Methyltransferase ◽

Epigenetic Signatures ◽

Aberrant Gene

Abstract Background Evidence of global heterochromatin decay and aberrant gene expression in models of physiological and premature ageing have long supported the “heterochromatin loss theory of ageing”, which proposes that ageing is aetiologically linked to, and accompanied by, a progressive, generalised loss of repressive epigenetic signatures. However, the remarkable plasticity of chromatin conformation suggests that the re-establishment of such marks could potentially revert the transcriptomic architecture of animal cells to a “younger” state, promoting longevity and healthspan. To expand our understanding of the ageing process and its connection to chromatin biology, we screened an RNAi library of chromatin-associated factors for increased longevity phenotypes. Results We identified the lysine demethylases jmjd-3.2 and utx-1, as well as the lysine methyltransferase mes-2 as regulators of both lifespan and healthspan in C. elegans. Strikingly, we found that both overexpression and loss of function of jmjd-3.2 and utx-1 are all associated with enhanced longevity. Furthermore, we showed that the catalytic activity of UTX-1, but not JMJD-3.2, is critical for lifespan extension in the context of overexpression. In attempting to reconcile the improved longevity associated with both loss and gain of function of utx-1, we investigated the alternative lifespan pathways and tissue specificity of longevity outcomes. We demonstrated that lifespan extension caused by loss of utx-1 function is daf-16 dependent, while overexpression effects are partially independent of daf-16. In addition, lifespan extension was observed when utx-1 was knocked down or overexpressed in neurons and intestine, whereas in the epidermis, only knockdown of utx-1 conferred improved longevity. Conclusions We show that the regulation of longevity by chromatin modifiers can be the result of the interaction between distinct factors, such as the level and tissue of expression. Overall, we suggest that the heterochromatin loss model of ageing may be too simplistic an explanation of organismal ageing when molecular and tissue-specific effects are taken into account.

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Loss-of-function of p53 isoform Δ113p53 accelerates brain aging in zebrafish

Cell Death and Disease ◽

10.1038/s41419-021-03438-9 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Ting Zhao ◽

Shengfan Ye ◽

Zimu Tang ◽

Liwei Guo ◽

Zhipeng Ma ◽

...

Keyword(s):

Replicative Senescence ◽

Brain Aging ◽

Ventricular Zone ◽

Human Fibroblasts ◽

Cell Lineage ◽

Lineage Tracing ◽

Dependent Manner ◽

Loss Of Function ◽

Antioxidant Genes ◽

Age Related

AbstractReactive oxygen species (ROS) stress has been demonstrated as potentially critical for induction and maintenance of cellular senescence, and been considered as a contributing factor in aging and in various neurological disorders including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). In response to low-level ROS stress, the expression of Δ133p53, a human p53 isoform, is upregulated to promote cell survival and protect cells from senescence by enhancing the expression of antioxidant genes. In normal conditions, the basal expression of Δ133p53 prevents human fibroblasts, T lymphocytes, and astrocytes from replicative senescence. It has been also found that brain tissues from AD and ALS patients showed decreased Δ133p53 expression. However, it is uncharacterized if Δ133p53 plays a role in brain aging. Here, we report that zebrafish Δ113p53, an ortholog of human Δ133p53, mainly expressed in some of the radial glial cells along the telencephalon ventricular zone in a full-length p53-dependent manner. EDU-labeling and cell lineage tracing showed that Δ113p53-positive cells underwent cell proliferation to contribute to the neuron renewal process. Importantly, Δ113p53M/M mutant telencephalon possessed less proliferation cells and more senescent cells compared to wild-type (WT) zebrafish telencephalon since 9-months old, which was associated with decreased antioxidant genes expression and increased level of ROS in the mutant telencephalon. More interestingly, unlike the mutant fish at 5-months old with cognition ability, Δ113p53M/M zebrafish, but not WT zebrafish, lost their learning and memory ability at 19-months old. The results demonstrate that Δ113p53 protects the brain from aging by its antioxidant function. Our finding provides evidence at the organism level to show that depletion of Δ113p53/Δ133p53 may result in long-term ROS stress, and finally lead to age-related diseases, such as AD and ALS in humans.

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Sudden complete or partial loss of function of the octavus-system in apparently normal persons

Acta Oto-Laryngologica ◽

10.3109/00016484409119921 ◽

1944 ◽

Vol 32 (5-6) ◽

pp. 407-429 ◽

Cited By ~ 114

Author(s):

A. De Kleyn

Keyword(s):

Loss Of Function ◽

Partial Loss

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NR5A2 Is One of 12 Transcription Factors Predicting Prognosis in HNSCC and Regulates Cancer Cell Proliferation in a p53-Dependent Manner

Frontiers in Oncology ◽

10.3389/fonc.2021.691318 ◽

2021 ◽

Vol 11 ◽

Author(s):

Kun Zhang ◽

Ming Xiao ◽

Xin Jin ◽

Hongyan Jiang

Keyword(s):

Overall Survival ◽

Survival Time ◽

Cancer Progression ◽

Risk Model ◽

Critical Role ◽

Disease Free Survival ◽

Dependent Manner ◽

Loss Of Function ◽

Free Survival ◽

Disease Free

Head and neck squamous cell carcinoma (HNSCC) rank seventh among the most common type of malignant tumor worldwide. Various evidences suggest that transcriptional factors (TFs) play a critical role in modulating cancer progression. However, the prognostic value of TFs in HNSCC remains unclear. Here, we identified a risk model based on a 12-TF signature to predict recurrence-free survival (RFS) in patients with HNSCC. We further analyzed the ability of the 12-TF to predict the disease-free survival time and overall survival time in HNSCC, and found that only NR5A2 down-regulation was strongly associated with shortened overall survival and disease-free survival time in HNSCC. Moreover, we systemically studied the role of NR5A2 in HNSCC and found that NR5A2 regulated HNSCC cell growth in a TP53 status-dependent manner. In p53 proficient cells, NR5A2 knockdown increased the expression of TP53 and activated the p53 pathway to enhance cancer cells proliferation. In contrast, NR5A2 silencing suppressed the growth of HNSCC cells with p53 loss/deletion by inhibiting the glycolysis process. Therefore, our results suggested that NR5A2 may serve as a promising therapeutic target in HNSCC harboring loss-of-function TP53 mutations.

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Bmmp influences wing shape by regulating anterior-posterior and proximal-distal axis development

10.1101/2021.07.26.453796 ◽

2021 ◽

Author(s):

Yunlong Zou ◽

Xin Ding ◽

Li Zhang ◽

Lifeng Xu ◽

Shubo Liang ◽

...

Keyword(s):

Molecular Mapping ◽

Wing Shape ◽

Wing Development ◽

Mrna Levels ◽

Nucleotide Polymorphisms ◽

Insect Wing ◽

Expression Of Genes ◽

Flight Capacity ◽

Null Mutants ◽

Anterior Posterior

Insect wings are subject to strong selective pressure, resulting in the evolution of remarkably diverse wing shapes that largely determine flight capacity. However, the genetic basis and regulatory mechanisms underlying wing shape development are not well understood. The silkworm Bombyx mori micropterous ( mp ) mutant exhibits shortened wing length and enlarged vein spacings , albeit without changes in total wing area. Thus, the mp mutant comprises a valuable genetic resource for studying wing shape development. In this study, we used molecular mapping to identify the gene responsible for the mp phenotype and designated it Bmmp . Phenotype-causing mutations were identified as indels and single nucleotide polymorphisms in non-coding regions. These mutations resulted in decreased Bmmp mRNA levels and changes in transcript isoform composition. Bmmp null mutants were generated by CRISPR/Cas9 and exhibited significantly smaller wings. By examining the expression of genes critical to wing development in wildtype and Bmmp null mutants, we found that Bm mp exerts its function by coordinately modulating anterior-posterior and proximal-distal axis development. We also studied a Drosophila mp mutant and found that Bmmp is functionally conserved in Drosophila . The Drosophila mp mutant strain exhibits curly wings of reduced size and a complete loss of flight capacity. Our results increase our understanding of the mechanisms underpinning insect wing development and reveal potential targets for pest control.

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Ras controls growth, survival and differentiation in the Drosophila eye by different thresholds of MAP kinase activity

Development ◽

10.1242/dev.128.9.1687 ◽

2001 ◽

Vol 128 (9) ◽

pp. 1687-1696 ◽

Cited By ~ 3

Author(s):

K. Halfar ◽

C. Rommel ◽

H. Stocker ◽

E. Hafen

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Kinase Activity ◽

Photoreceptor Cells ◽

Loss Of Function ◽

Cellular Functions ◽

Partial Loss ◽

Cycle Progression ◽

Mapk Activity ◽

Dividing Cells

Ras mediates a plethora of cellular functions during development. In the developing eye of Drosophila, Ras performs three temporally separate functions. In dividing cells, it is required for growth but is not essential for cell cycle progression. In postmitotic cells, it promotes survival and subsequent differentiation of ommatidial cells. In the present paper, we have analyzed the different roles of Ras during eye development by using molecularly defined complete and partial loss-of-function mutations of Ras. We show that the three different functions of Ras are mediated by distinct thresholds of MAPK activity. Low MAPK activity prolongs cell survival and permits differentiation of R8 photoreceptor cells while high or persistent MAPK activity is sufficient to precociously induce R1-R7 photoreceptor differentiation in dividing cells.

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Small Molecule Stabilization of PINK-1/PINK1 Improves Neurodegenerative Disease

10.1101/2021.06.07.447442 ◽

2021 ◽

Author(s):

Elissa Tjahjono ◽

Jingqi Pei ◽

Alexey V Revtovich ◽

Terri-Jeanne E Liu ◽

Alisha Swadi ◽

...

Keyword(s):

Neurodegenerative Disease ◽

Dependent Manner ◽

Loss Of Function ◽

Mitochondrial Fragmentation ◽

Atp Production ◽

C Elegans ◽

Mitochondrial Homeostasis ◽

Phenotypic Screen ◽

Gfp Reporter ◽

Common Causes

Macroautophagic recycling of dysfunctional mitochondria, known as mitophagy, is essential for mitochondrial homeostasis and cell viability. Accumulation of defective mitochondria and impaired mitophagy have been widely implicated in many neurodegenerative diseases, and loss-of-function mutations of two regulators of mitophagy, PINK1 and Parkin, are amongst the most common causes of recessive Parkinson's disease. Activation of mitophagy via pharmacological treatments may be a feasible approach for combating neurodegeneration. In this effort, we screened ~45,000 small molecules for the ability to activate mitophagy. A high-throughput, whole-organism, phenotypic screen was conducted by monitoring stabilization of PINK-1/PINK1, a key event in mitophagy activation, in a Caenorhabditis elegans strain carrying a Ppink-1::PINK-1::GFP reporter. We obtained eight hits that induced mitophagy, as evidenced by increased mitochondrial fragmentation and autophagosome formation. Several of the compounds also reduced ATP production, oxygen consumption, mitochondrial mass, and/or mitochondrial membrane potential. Importantly, we found that treatment with two compounds, which we named PS83 and PS106 (more commonly known as sertraline) reduced neurodegenerative disease phenotypes (including delayed paralysis in a C. elegans Alzheimer's model) in a PINK-1/PINK1-dependent manner. This report presents a promising step toward the identification of compounds that will stimulate mitochondrial turnover.

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