Defects in the Neuroendocrine Axis Contribute to Global Development Delay in a Drosophila Model of NGLY1 Deficiency

G3 Genes Genomes Genetics, Год журнала: 2018, Номер 8(7), С. 2193 - 2204

Опубликована: Май 7, 2018

N-glycanase 1 (NGLY1) Deficiency is a rare monogenic multi-system disorder first described in 2014. NGLY1 evolutionarily conserved model organisms. Here we conducted natural history study and chemical-modifier screen on the Drosophila melanogaster homolog, Pngl We generated new fly of Deficiency, engineered with nonsense mutation at codon 420 that results truncation C-terminal carbohydrate-binding PAW domain. Homozygous mutant animals exhibit global development delay, pupal lethality small body size as adults. developed 96-well-plate, image-based, quantitative assay larval for use 2,650-member Microsource Spectrum compound library FDA approved drugs, bioactive tool compounds, products. found cholesterol-derived ecdysteroid molting hormone 20-hydroxyecdysone (20E) partially rescued developmental delay homozygotes. Targeted expression human transgene to tissues involved ecdysteroidogenesis, e.g., prothoracic gland, also rescues Finally, proteasome inhibitor bortezomib potent enhancer our model, evidence defective "bounce-back" response observed nematode cellular models Deficiency. Together, these demonstrate therapeutic relevance drug discovery gene modifier screens.

Язык: Английский

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Interorgan communication in the control of metamorphosis

Current Opinion in Insect Science, Год журнала: 2020, Номер 43, С. 54 - 62

Опубликована: Окт. 23, 2020

Язык: Английский

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Bone morphogenetic protein signaling: the pathway and its regulation

Genetics, Год журнала: 2023, Номер 226(2)

Опубликована: Дек. 20, 2023

Abstract In the mid-1960s, bone morphogenetic proteins (BMPs) were first identified in extracts of to have remarkable ability induce heterotopic bone. When Drosophila gene decapentaplegic (dpp) was share sequence similarity with mammalian BMP2/BMP4 late-1980s, it became clear that secreted BMP ligands can mediate processes other than formation. Following this discovery, collaborative efforts between geneticists and biochemists made use strengths their respective model systems identify signaling components delineate pathway. The conduct genetic modifier screens relative ease critical identifying intracellular signal transducers for related transforming growth factor-beta/activin Such also revealed a host genes encode core regulators review, we provide historical account exciting time discovery discuss how field has advanced over past 30 years. We learned while pathway is quite simple, composed 3 (ligand, receptor, transducer), behind versatility lies multiple layers regulation ensures precise tissue-specific output. sampling these discoveries highlight many questions remain be answered fully understand complexity signaling.

Язык: Английский

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Muscle-derived Dpp regulates feeding initiation via endocrine modulation of brain dopamine biosynthesis

Genes & Development, Год журнала: 2019, Номер 34(1-2), С. 37 - 52

Опубликована: Дек. 12, 2019

In animals, the brain regulates feeding behavior in response to local energy demands of peripheral tissues, which secrete orexigenic and anorexigenic hormones. Although skeletal muscle is a key tissue, it remains unknown whether muscle-secreted hormones regulate feeding.

Язык: Английский

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Systemic signalling and local effectors in developmental stability, body symmetry, and size

Cell Stress, Год журнала: 2018, Номер 2(12), С. 340 - 361

Опубликована: Дек. 4, 2018

Systemic signalling and local effectors in developmental stability, body symmetry, size – Symmetric growth the origins of fluctuating asymmetry are unresolved phenomena biology. Small, sometimes noticeable, deviations from perfect bilateral symmetry reflect vulnerability development to perturbations. The degree is related magnitude perturbations ability an individual cope with them. As left right sides were presumed be genetically identical, traditionally attributed non-genetic effects such as environmental noise. In this review, we draw attention other possible sources variability, especially somatic mutations transposons. Mutations a major source phenotypic variability recent genomic data have highlighted ubiquitous, even phenotypically normal individuals. We discuss importance factors that responsible for buffering stabilizing genome (...)

Язык: Английский

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Muscle-derived Myoglianin regulates Drosophila imaginal disc growth

eLife, Год журнала: 2020, Номер 9

Опубликована: Июль 7, 2020

Organ growth and size are finely tuned by intrinsic extrinsic signaling molecules. In Drosophila, the BMP family member Dpp is produced in a limited set of imaginal disc cells functions as classic morphogen to regulate pattern diffusing throughout discs. However, role TGFβ/Activin-like ligands control remains ill-defined. Here, we demonstrate that Myoglianin (Myo), an Activin member, close homolog mammalian Myostatin (Mstn), muscle-derived factor uses canonical dSmad2-mediated wing size. We propose Myo myokine helps mediate allometric relationship between muscles their associated appendages.

Язык: Английский

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Imaginal Disc Regeneration: Something Old, Something New

Cold Spring Harbor Perspectives in Biology, Год журнала: 2021, Номер unknown, С. a040733 - a040733

Опубликована: Дек. 6, 2021

Melanie I. Worley and Iswar K. Hariharan Department of Molecular Cell Biology, University California, Berkeley, California 94720-3200, USA Correspondence: ikh{at}berkeley.edu

Язык: Английский

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Steroid signaling in autophagy

Journal of Molecular Biology, Год журнала: 2025, Номер unknown, С. 169134 - 169134

Опубликована: Апрель 1, 2025

Autophagy is a conserved cellular process essential for homeostasis and development that plays central role in the degradation recycling of components. Recent studies reveal bidirectional interactions between autophagy steroid-hormone signaling. Steroids are signaling molecules synthesized from cholesterol regulate key physiological developmental processes - including autophagic activity. Conversely, other work demonstrates regulates steroid production by controlling availability precursor sterol substrate. Insights Drosophila mammalian models provide compelling evidence conservation these mechanisms across species. In this review we explore how hormones modulate diverse tissues contexts, such as metabolism disease, discuss advances our understanding autophagy's regulatory hormone production. We examine implications health disease offer perspectives on potential harnessing functionality addressing cholesterol-related disorders.

Язык: Английский

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Network‐regulated organ allometry: The developmental regulation of morphological scaling

Wiley Interdisciplinary Reviews Developmental Biology, Год журнала: 2020, Номер 10(3)

Опубликована: Июнь 21, 2020

Abstract Morphological scaling relationships, or allometries, describe how traits grow coordinately and covary among individuals in a population. The developmental regulation of is essential to generate correctly proportioned adults across range body sizes, while the mis‐regulation may result congenital birth defects. Research over several decades has identified mechanisms that regulate size individual traits. Nevertheless, we still have poor understanding these work together correlated variation response environmental genetic variation. Conceptually, morphological can be generated by size‐regulatory factors act directly on multiple growing (trait‐autonomous scaling), indirectly via hormones produced central endocrine organs (systemically regulated there are number well‐established examples such mechanisms. There much less evidence, however, actually acts natural populations. More recent studies indicate themselves growth other body. This suggests covariation trait network‐regulated respond changes Testing this hypothesis, one main challenges scaling, requires connecting elucidated laboratory with patterns observed world. article categorized under: Establishment Spatial Temporal Patterns > Regulation Size, Proportion, Timing Comparative Development Evolution Organ System Comparisons Between Species

Язык: Английский

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Tracing the NGLY1 footprints: insights from Drosophila

The Journal of Biochemistry, Год журнала: 2021, Номер 171(2), С. 153 - 160

Опубликована: Июль 14, 2021

Recessive mutations in human N-glycanase 1 (NGLY1) cause a multisystem disorder with various phenotypes including global developmental delay. One of the models utilized to understand biology NGLY1 and pathophysiology deficiency is Drosophila melanogaster, well-established, genetically tractable organism broadly used study biological processes diseases. Loss homolog (Pngl) causes host delay lethality. Phenotypic, transcriptomic genome-wide association analyses on have revealed links between several critical cellular pathways/processes. Further, repurposing screens Food Drug Administration (FDA)-approved drugs identified potential candidates ameliorate some Pngl-mutant phenotypes. Here, we will summarize insights gained into functions from studies. We hope that current review article encourage additional studies other model systems towards establishing therapeutic strategy for patients.

Язык: Английский

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