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1.
Front Toxicol ; 4: 815754, 2022.
Article in English | MEDLINE | ID: mdl-35295214

ABSTRACT

The last decade has seen the adverse outcome pathways (AOP) framework become one of the most powerful tools in chemical risk assessment, but the development of new AOPs remains a slow and manually intensive process. Here, we present a faster approach for AOP generation, based on manually curated causal toxicological networks. As a case study, we took a recently published zebrafish developmental neurotoxicity network, which contains causally connected molecular events leading to neuropathologies, and developed two new adverse outcome pathways: Inhibition of Fyna (Src family tyrosine kinase A) leading to increased mortality via decreased eye size (AOP 399 on AOP-Wiki) and GSK3beta (Glycogen synthase kinase 3 beta) inactivation leading to increased mortality via defects in developing inner ear (AOP 410). The approach consists of an automatic separation of the toxicological network into candidate AOPs, filtering the AOPs according to available evidence and length as well as manual development of new AOPs and weight-of-evidence evaluation. The semiautomatic approach described here provides a new opportunity for fast and straightforward AOP development based on large network resources.

2.
Front Genet ; 12: 652632, 2021.
Article in English | MEDLINE | ID: mdl-34211495

ABSTRACT

Adverse outcomes that result from chemical toxicity are rarely caused by dysregulation of individual proteins; rather, they are often caused by system-level perturbations in networks of molecular events. To fully understand the mechanisms of toxicity, it is necessary to recognize the interactions of molecules, pathways, and biological processes within these networks. The developing brain is a prime example of an extremely complex network, which makes developmental neurotoxicity one of the most challenging areas in toxicology. We have developed a systems toxicology method that uses a computable biological network to represent molecular interactions in the developing brain of zebrafish larvae. The network is curated from scientific literature and describes interactions between biological processes, signaling pathways, and adverse outcomes associated with neurotoxicity. This allows us to identify important signaling hubs, pathway interactions, and emergent adverse outcomes, providing a more complete understanding of neurotoxicity. Here, we describe the construction of a zebrafish developmental neurotoxicity network and its validation by integration with publicly available neurotoxicity-related transcriptomic datasets. Our network analysis identified consistent regulation of tumor suppressors p53 and retinoblastoma 1 (Rb1) as well as the oncogene Krüppel-like factor (Klf8) in response to chemically induced developmental neurotoxicity. The developed network can be used to interpret transcriptomic data in a neurotoxicological context.

3.
Blood ; 128(26): 3052-3060, 2016 12 29.
Article in English | MEDLINE | ID: mdl-27827822

ABSTRACT

During hematopoiesis, the balance between proliferation, differentiation, and apoptosis is tightly regulated in order to maintain homeostasis. Failure in these processes can ultimately lead to uncontrolled proliferation and leukemia. Phosphatase and tensin homolog (PTEN) is one of the molecular pathways involved in this balance. By opposing PI3-kinases, PTEN inhibits proliferation and promotes differentiation and is thus considered a tumor suppressor. Indeed, PTEN is frequently mutated in many cancers, including leukemias. Loss of PTEN often leads to lymphoid cancers. However, little is known about the molecular events that regulate PTEN signaling during lymphopoiesis. In this study, we used zebrafish to address this. We report that N-myc downstream-regulated gene 1b (ndrg1b) rescues lymphoid differentiation after PTEN inhibition. We also show that a previously uncharacterized gene, fam49ab, inhibits T-cell differentiation, a phenotype that can be rescued by ndrg1b We propose that ndrg1b and fam49ab are 2 new modulators of PTEN signaling that control lymphoid differentiation in the zebrafish thymus.


Subject(s)
Cell Cycle Proteins/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Lymphopoiesis , PTEN Phosphohydrolase/metabolism , T-Lymphocytes/metabolism , Zebrafish Proteins/metabolism , Zebrafish/metabolism , Animals , Cell Cycle Proteins/genetics , Cell Differentiation/drug effects , Cell Differentiation/genetics , Embryo, Nonmammalian/drug effects , Embryo, Nonmammalian/metabolism , Hematopoiesis/drug effects , Homeodomain Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Lymphopoiesis/drug effects , Morpholinos/pharmacology , Multigene Family , Mutation/genetics , Phenotype , Phosphatidylinositol 3-Kinases/metabolism , Signal Transduction/drug effects , T-Lymphocytes/drug effects , Thymocytes/drug effects , Thymocytes/metabolism , Thymus Gland/metabolism , Zebrafish/embryology
4.
Development ; 141(16): 3266-76, 2014 Aug.
Article in English | MEDLINE | ID: mdl-25063452

ABSTRACT

Here, we exploit the spatial separation of temporal events of neural differentiation in the elongating chick body axis to provide the first analysis of transcriptome change in progressively more differentiated neural cell populations in vivo. Microarray data, validated against direct RNA sequencing, identified: (1) a gene cohort characteristic of the multi-potent stem zone epiblast, which contains neuro-mesodermal progenitors that progressively generate the spinal cord; (2) a major transcriptome re-organisation as cells then adopt a neural fate; and (3) increasing diversity as neural patterning and neuron production begin. Focussing on the transition from multi-potent to neural state cells, we capture changes in major signalling pathways, uncover novel Wnt and Notch signalling dynamics, and implicate new pathways (mevalonate pathway/steroid biogenesis and TGFß). This analysis further predicts changes in cellular processes, cell cycle, RNA-processing and protein turnover as cells acquire neural fate. We show that these changes are conserved across species and provide biological evidence for reduced proteasome efficiency and a novel lengthening of S phase. This latter step may provide time for epigenetic events to mediate large-scale transcriptome re-organisation; consistent with this, we uncover simultaneous downregulation of major chromatin modifiers as the neural programme is established. We further demonstrate that transcription of one such gene, HDAC1, is dependent on FGF signalling, making a novel link between signals that control neural differentiation and transcription of a core regulator of chromatin organisation. Our work implicates new signalling pathways and dynamics, cellular processes and epigenetic modifiers in neural differentiation in vivo, identifying multiple new potential cellular and molecular mechanisms that direct differentiation.


Subject(s)
Chromatin/metabolism , Neurogenesis/physiology , Neurons/cytology , Transcriptome , Animals , Body Patterning , Cell Cycle , Cell Differentiation , Cell Lineage , Chick Embryo , Epigenesis, Genetic , Fibroblast Growth Factors/metabolism , Gene Expression Regulation, Developmental , Histone Deacetylase 1/metabolism , Mice , Oligonucleotide Array Sequence Analysis , Sequence Analysis, RNA , Signal Transduction , Spinal Cord/embryology , Time Factors , Transforming Growth Factor beta/metabolism
6.
Dev Biol ; 338(2): 215-25, 2010 Feb 15.
Article in English | MEDLINE | ID: mdl-20004186

ABSTRACT

Regulated neuron production within the vertebrate nervous system relies on input from multiple signalling pathways. Work in the Drosophila retina has demonstrated that PI3-kinase and downstream TOR signalling regulate the timing of photoreceptor differentiation; however, the function of such signals during vertebrate neurogenesis is not well understood. Here we show that mutant mice lacking PKB activity downstream of PDK1, the master kinase of the PI3-kinase pathway, exhibit deficient neuron production. We further demonstrate expression of PI3-kinase signalling components and active PKB and TOR signalling in the chick spinal cord, an early site of neurogenesis. Neuron production was also attenuated in the chick neural tube following exposure to small molecule inhibitors of PI3-kinase (LY294002) or TOR (Rapamycin) activity. Furthermore, Rapamycin repressed expression of early neuronal differentiation genes, such as Ngn2, but did not inhibit expression of Sox1B genes characteristic of proliferating neural progenitors. In addition, some cells expressing an early neuronal marker were mis-localised at the ventricular surface in the presence of Rapamycin and remained aberrantly within the cell cycle. These findings suggest that TOR signalling is necessary to initiate neuronal differentiation and that it may facilitate coordination of cell cycle and differentiation programmes. In contrast, stimulating PI3-kinase signalling did not increase neuron production, suggesting that such activity is simply permissive for vertebrate neurogenesis.


Subject(s)
Cell Differentiation , Intracellular Signaling Peptides and Proteins/metabolism , Neural Tube/cytology , Neurons/cytology , Phosphatidylinositol 3-Kinases/metabolism , Protein Serine-Threonine Kinases/metabolism , Signal Transduction , Animals , Cell Cycle , Cell Differentiation/genetics , Chick Embryo , Mice , Mice, Mutant Strains , Neural Tube/metabolism , Neurogenesis , Sirolimus/pharmacology , TOR Serine-Threonine Kinases
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