From phenologs to silent suppressors: Identifying potential therapeutic targets for human disease

Golden, Andy

doi:10.1002/mrd.22880

Cited by 15 publications

(9 citation statements)

References 94 publications

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“…To analyze such signals, we used let-60(n1046 gf ) , a moderately activating G13E mutation analogous to mutations found in a subset of mammalian cancers [49]. In this background, gain and loss of the RAL-1 2°-promoting signal resulted in decrease and increase of ectopic 1° cells, respectively [10, 12].…”

Section: Resultsmentioning

confidence: 99%

Developmental fidelity is imposed by genetically separable RalGEF activities that mediate opposing signals

et al. 2019

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The six C . elegans vulval precursor cells (VPCs) are induced to form the 3°-3°-2°-1°-2°-3° pattern of cell fates with high fidelity. In response to EGF signal, the LET-60/Ras-LIN-45/Raf-MEK-2/MEK-MPK-1/ERK canonical MAP kinase cascade is necessary to induce 1° fate and synthesis of DSL ligands for the lateral Notch signal. In turn, LIN-12/Notch receptor is necessary to induce neighboring cells to become 2°. We previously showed that, in response to graded EGF signal, the modulatory LET-60/Ras-RGL-1/RalGEF-RAL-1/Ral signal promotes 2° fate in support of LIN-12. In this study, we identify two key differences between RGL-1 and RAL-1. First, deletion of RGL-1 confers no overt developmental defects, while previous studies showed RAL-1 to be essential for viability and fertility. From this observation, we hypothesize that the essential functions of RAL-1 are independent of upstream activation. Second, RGL-1 plays opposing and genetically separable roles in VPC fate patterning. RGL-1 promotes 2° fate via canonical GEF-dependent activation of RAL-1. Conversely, RGL-1 promotes 1° fate via a non-canonical GEF-independent activity. Our genetic epistasis experiments are consistent with RGL-1 functioning in the modulatory 1°-promoting AGE-1/PI3-Kinase-PDK-1-AKT-1 cascade. Additionally, animals lacking RGL-1 experience 15-fold higher rates of VPC patterning errors compared to the wild type. Yet VPC patterning in RGL-1 deletion mutants is not more sensitive to environmental perturbations. We propose that RGL-1 functions to orchestrate opposing 1°- and 2°-promoting modulatory cascades to decrease developmental stochasticity. We speculate that such switches are broadly conserved but mostly masked by paralog redundancy or essential functions.

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Section: Resultsmentioning

confidence: 99%

Developmental fidelity is imposed by genetically separable RalGEF activities that mediate opposing signals

et al. 2019

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“…To detect such signals, we use let-60(n1046gf), a moderately activating G13E mutation analogous to mutations found in some mammalian cancers (55). In this background, gain and loss of the RAL-1 2˚-promoting signal resulted in decrease and increase of ectopic 1˚ cells, respectively.…”

Section: Resultsmentioning

confidence: 99%

Developmental fidelity imposed by the RGL-1 “Balanced Switch” mediating opposing signals

Shin

Braendle

Monahan³

et al. 2018

Preprint

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The six C. elegans vulval precursor cells (VPCs) are induced to form the 3˚-3˚-2˚-1˚-2˚-3˚ pattern of cell fates with high fidelity. In response to EGF signal, the LET-60/Ras-LIN-45/Raf-MEK-2/MEK-MPK-1/ERK canonical MAP kinase cascade is necessary to induce 1˚ fate and synthesis of DSL ligands. In turn, LIN-12/Notch signal is necessary to induce neighboring cells to become 2˚. We previously showed that, in response to lower dose of EGF signal, the modulatory LET-60/Ras-RGL-1/RalGEF-RAL-1/Ral signal promotes 2˚ fate in support of LIN-12. In this study we identify two key differences between RGL-1 and RAL-1 functions. First, deletion of RGL-1 confers no overt developmental defects, while previous studies showed RAL-1 to be essential for viability and fertility. From this observation we hypothesize that the developmentally essential functions of RAL-1 are independent of upstream activation. Second, RGL-1 plays opposing and genetically separable roles in VPC fate patterning. RGL-1 promotes 2˚ fate via canonical GEFdependent activation of RAL-1 and 1˚ fate via a non-canonical GEF-independent activity.Our genetic epistasis experiments are consistent with RGL-1 functioning in the modulatory 1˚-promoting AGE-1/PI3-Kinase-PDK-1-AKT-1 cascade. Additionally, animals without RGL-1 experience 15-fold higher rates of VPC patterning errors compared to the wild type. Yet VPC patterning in RGL-1 deletion mutants is not more sensitive to environmental perturbations. We propose that RGL-1 functions as a RGL-1/RalGEF in VPC fate patterning Shin et al."Balanced Switch" that orchestrates opposing 1˚-and 2˚-promoting modulatory cascades to decrease inappropriate fate decisions. We speculate that such switches are broadly conserved but mostly masked by paralog redundancy or essential genes.

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“…Model organisms, including Mus sp . (laboratory mouse), Saccharomyces cerevisiae , Drosophila melanogaster , Caenorhabditis elegans , Danio rerio , and Rattus norvegicus , and model systems less commonly used have provided insights into the biological processes that underlie human health and disease, and have contributed to the development of diagnoses and treatments for genetic diseases (Iannaccone and Jacob 2009; Phillips and Westerfield 2014; Hamza et al 2015; Kachroo et al 2015; Strange 2016; Ugur et al 2016; Bonini and Berger 2017; Golden 2017; Sen and Cox 2017; Wangler et al 2017; Apfeld and Alper 2018; Ingham 2018; Nadeau and Auwerx 2019; Smith et al 2019).…”

Section: A Brief History Of Model Organism Databases and The Gene Ontmentioning

confidence: 99%

The Alliance of Genome Resources: Building a Modern Data Ecosystem for Model Organism Databases

Bult¹,

Blake²,

Calvi³

et al. 2019

Genetics

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Model organisms are essential experimental platforms for discovering gene functions, defining protein and genetic networks, uncovering functional consequences of human genome variation, and for modeling human disease. For decades, researchers who use model organisms have relied on Model Organism Databases (MODs) and the Gene Ontology Consortium (GOC) for expertly curated annotations, and for access to integrated genomic and biological information obtained from the scientific literature and public data archives. Through the development and enforcement of data and semantic standards, these genome resources provide rapid access to the collected knowledge of model organisms in human readable and computation-ready formats that would otherwise require countless hours for individual researchers to assemble on their own. Since their inception, the MODs for the predominant biomedical model organisms [Mus sp. (laboratory mouse), Saccharomyces cerevisiae, Drosophila melanogaster, Caenorhabditis elegans, Danio rerio, and Rattus norvegicus] along with the GOC have operated as a network of independent, highly collaborative genome resources. In 2016, these six MODs and the GOC joined forces as the Alliance of Genome Resources (the Alliance). By implementing shared programmatic access methods and data-specific web pages with a unified “look and feel,” the Alliance is tackling barriers that have limited the ability of researchers to easily compare common data types and annotations across model organisms. To adapt to the rapidly changing landscape for evaluating and funding core data resources, the Alliance is building a modern, extensible, and operationally efficient “knowledge commons” for model organisms using shared, modular infrastructure.

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From phenologs to silent suppressors: Identifying potential therapeutic targets for human disease

Cited by 15 publications

References 94 publications

Developmental fidelity is imposed by genetically separable RalGEF activities that mediate opposing signals

Developmental fidelity is imposed by genetically separable RalGEF activities that mediate opposing signals

Developmental fidelity imposed by the RGL-1 “Balanced Switch” mediating opposing signals

The Alliance of Genome Resources: Building a Modern Data Ecosystem for Model Organism Databases

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