The sex-limited effects of mutations in the EGFR and TGF-β signaling pathways on shape and size sexual dimorphism and allometry in the Drosophila wing

Testa, Nicholas D.; Dworkin, Ian

doi:10.1007/s00427-016-0534-7

Cited by 26 publications

(15 citation statements)

References 71 publications

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“…4 B and C). This is also consistent with a recent report that fly wings display sex-dependent effects in different genetic backgrounds (43). Additionally, multiple studies have suggested a role of sex on the severity of defects in individuals with RASopathies.…”

Section: Resultssupporting

confidence: 92%

In vivo severity ranking of Ras pathway mutations associated with developmental disorders

Jindal

Goyal

Yamaya

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Germ-line mutations in components of the Ras/MAPK pathway result in developmental disorders called RASopathies, affecting about 1/1,000 human births. Rapid advances in genome sequencing make it possible to identify multiple disease-related mutations, but there is currently no systematic framework for translating this information into patient-specific predictions of disease progression. As a first step toward addressing this issue, we developed a quantitative, inexpensive, and rapid framework that relies on the early zebrafish embryo to assess mutational effects on a common scale. Using this assay, we assessed 16 mutations reported in MEK1, a MAPK kinase, and provide a robust ranking of these mutations. We find that mutations found in cancer are more severe than those found in both RASopathies and cancer, which, in turn, are generally more severe than those found only in RASopathies. Moreover, this rank is conserved in other zebrafish embryonic assays and Drosophila-specific embryonic and adult assays, suggesting that our ranking reflects the intrinsic property of the mutant molecule. Furthermore, this rank is predictive of the drug dose needed to correct the defects. This assay can be readily used to test the strengths of existing and newly found mutations in MEK1 and other pathway components, providing the first step in the development of rational guidelines for patient-specific diagnostics and treatment of RASopathies.T he Ras/MAPK (rat sarcoma/mitogen-activated protein kinase) signaling pathway is involved in essentially all aspects of organismal development, from the first cell divisions in the early embryo to postnatal development and growth (1-3). Given its critical function, it is not surprising that deregulated Ras/ MAPK signaling, resulting from either genetic or environmental perturbations, can lead to developmental abnormalities. A large class of such abnormalities, known as RASopathies, is associated with activating germ-line mutations in many components of the Ras pathway (4). Estimated to affect 1/1,000 human births, these abnormalities are characterized by a broad spectrum of phenotypes, including cardiac defects, craniofacial dysmorphisms, and neurocognitive delays (4). Although the origins of these phenotypes are still poorly understood, studies of model organisms show that many of the observed structural and functional defects can indeed be mimicked by targeted introduction of mutations found in RASopathies (5). Hundreds of such mutations have already been identified, and many more are likely to be discovered by the sequencing of affected individuals (6).Importantly, these studies identify new mutations in the very same components that are mutated in cancer and have been extensively studied both in vitro and in vivo (7-9). In particular, multiple new mutations were identified in MEK1, a MAPK kinase (10) and an important target for anticancer therapeutics (11)(12)(13)(14)(15)(16)(17)(18)(19). Because it is commonly believed that cancer mutations would be embryonic lethal when inherited through t...

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Section: Resultssupporting

confidence: 92%

In vivo severity ranking of Ras pathway mutations associated with developmental disorders

Jindal

Goyal

Yamaya

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…While these findings implicated multiple genes within each CNV region towards conserved cellular processes in neuronal tissues, the conserved role of these genes in non-neuronal tissues is not well understood. The Drosophila wing is an effective model system to evaluate such developmental defects, as key components of conserved signaling pathways, such as Notch, epidermal growth factor receptor (EGFR), Hegdehog, and Wnt pathways, were identified using fly wing models [32][33][34][35][36][37][38]. Although fly wing phenotypes cannot be directly translated to human phenotypes, defects observed in fly wings can be used to assess how homologs of human disease genes alter conserved cellular and developmental mechanisms.…”

Section: Plos Geneticsmentioning

confidence: 99%

Drosophila models of pathogenic copy-number variant genes show global and non-neuronal defects during development

et al. 2020

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While rare pathogenic copy-number variants (CNVs) are associated with both neuronal and non-neuronal phenotypes, functional studies evaluating these regions have focused on the molecular basis of neuronal defects. We report a systematic functional analysis of non-neuronal defects for homologs of 59 genes within ten pathogenic CNVs and 20 neurodevelopmental genes in Drosophila melanogaster. Using wing-specific knockdown of 136 RNA interference lines, we identified qualitative and quantitative phenotypes in 72/79 homologs, including 21 lines with severe wing defects and six lines with lethality. In fact, we found that 10/31 homologs of CNV genes also showed complete or partial lethality at larval or pupal stages with ubiquitous knockdown. Comparisons between eye and wing-specific knockdown of 37/45 homologs showed both neuronal and non-neuronal defects, but with no correlation in the severity of defects. We further observed disruptions in cell proliferation and apoptosis in larval wing discs for 23/27 homologs, and altered Wnt, Hedgehog and Notch signaling for 9/14 homologs, including AATF/Aatf, PPP4C/Pp4-19C, and KIF11/Klp61F. These findings were further supported by tissue-specific differences in expression patterns of human CNV genes, as well as connectivity of CNV genes to signaling pathway genes in brain, heart and kidney-specific networks. Our findings suggest that multiple genes within each CNV differentially affect both global and tissue-specific developmental processes within conserved pathways, and that their roles are not restricted to neuronal functions.

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“…Implementing these approaches demonstrates size and shape differences between male and female populations of Drosophila via systematic analysis of features extracted. In particular, females had significantly larger wings (p-value < 0.001) consistent with sexual dimorphism of insulin signaling activity (Testa and Dworkin 2016) while males had significantly larger trichome densities (p-value < 0.001). We also show how variable regulation of growth is necessary for maintaining perfect scaling of anatomical axes such as the AP axis and PD axis of the wing.…”

Section: Mapper Provides Multiplexed Analysis Tools For High Dimensiomentioning

confidence: 68%

“…The high dimensional morphometric fingerprint generated by MAPPER separates the male and female population of wings (Figure 2E,G). The sex-based difference in patterning and size of adult Drosophila melanogaster wing is known and well studied (Testa and Dworkin 2016). We also show that the EFD-based features can be used to probe into this sex-related shape changes more locally (Figure 2H).…”

Section: Resultsmentioning

confidence: 99%

MAPPER: A new image analysis pipeline unmasks differential regulation ofDrosophilawing features

Kumar

Huizar

Robinett

et al. 2020

Preprint

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SummaryPhenomics requires quantification of large volumes of image data, necessitating high throughput image processing approaches. Existing image processing pipelines for Drosophila wings, a powerful model for studying morphogenesis, are limited in speed, versatility, and precision. To overcome these limitations, we developed MAPPER, a fully-automated machine learning-based pipeline that quantifies high dimensional phenotypic signatures, with each dimension representing a unique morphological feature. MAPPER magnifies the power of Drosophila genetics by rapidly identifying subtle phenotypic differences in sample populations. To demonstrate its widespread utility, we used MAPPER to reveal new insights connecting patterning and growth across Drosophila genotypes and species. The morphological features extracted using MAPPER identified the presence of a uniform scaling of proximal-distal axis length across four different species of Drosophila. Observation of morphological features extracted by MAPPER from Drosophila wings by modulating insulin signaling pathway activity revealed the presence of a scaling gradient across the anterior-posterior axis. Additionally, batch processing of samples with MAPPER revealed a key function for the mechanosensitive calcium channel, Piezo, in regulating bilateral symmetry and robust organ growth. MAPPER is an open source tool for rapid analysis of large volumes of imaging data. Overall, MAPPER provides new capabilities to rigorously and systematically identify genotype-to-phenotype relationships in an automated, high throughput fashion.Graphical abstract

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The sex-limited effects of mutations in the EGFR and TGF-β signaling pathways on shape and size sexual dimorphism and allometry in the Drosophila wing

Cited by 26 publications

References 71 publications

In vivo severity ranking of Ras pathway mutations associated with developmental disorders

In vivo severity ranking of Ras pathway mutations associated with developmental disorders

Drosophila models of pathogenic copy-number variant genes show global and non-neuronal defects during development

MAPPER: A new image analysis pipeline unmasks differential regulation ofDrosophilawing features

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