Analysis of transient hypermorphic activity of E(spl)D during R8 specification

Majot, Adam T.; Bidwai, Ashok P.

doi:10.1371/journal.pone.0186439

Cited by 2 publications

(10 citation statements)

References 56 publications

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“…In WT, E(spl) are expressed dynamically across the MF (Fig. 8A; Baker et al, 1996; Majot and Bidwai, 2017). In aop clones, E(spl) immunolabeling resembles WT (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…E(spl) D encodes a truncated protein variant which lacks the regulatory C-terminal domain, producing a constitutively active form of M8 (Tietze et al, 1992; Nagel et al, 1999; Kahali et al, 2010). Despite being hypermorphic, E(spl) D alone elicits only minor morphological eye defects as compared to mutations that perturb N or EGFR signaling (Majot and Bidwai, 2017; Li et al, 2003; Lesokhin et al, 1999). Thus, if MAPK is required for the repression of Ato, additional targets than M8 likely exist.…”

Section: Introductionmentioning

confidence: 99%

“…Ato then induces the N pathway (Baonza and Freeman, 2001), which, in turn, directs subsequent patterning stages of Ato (Li and Baker, 2001). The enhancement of IGs during stage-2 features two discrete modes: early stage-2 presumed to be driven by ato-3’ , and late stage-2 driven primarily by 5’-ato (Jarman et al, 1994; Sun et al, 1998; Majot and Bidwai, 2017). In addition to its neurogenic role, N signaling also represses Ato, facilitating R8 individuation.…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies demonstrate that the proneural N signal occurs independently of Su(H) (Li and Baker, 2001). E(spl) is required for the onset of stage-3 Ato patterning, in which E(spl) antagonize Ato via the 5’ enhancer (Majot and Bidwai, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…To date, only E(spl)M8 (referred to as M8) has emerged as an apparent genetic link between N and EGFR-MAPK (Bandyopadhyay et al, 2016, Majot et al, 2015). Both genetic and biochemical evidence suggest that M8 directly antagonizes Ato via its 5’ enhancer following the formation of IGs (Majot and Bidwai, 2017, Karandikar et al, 2004, Kahali, et al, 2010). N and Su(H) are required for the expression of M8 and genetic evidence suggests that MAPK phosphorylates the C-terminal domain of M8 to potentiate M8’s repression of Ato (Bandyopadhyay et al, 2016; Bose et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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DrosophilaAop imposes a delay on E(spl)-mediated repression of Ato during R8 specification

et al. 2019

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22Drosophila retinal patterning requires the expression of Atonal (Ato) through coordinated 23 regulation of 5' and 3' enhancer modules. ato-3' directs initial expression of Ato which then 24 directs autoregulation via 5'-ato. Notch (N) signaling also regulates 5'-ato, first enhancing Ato 25 expression and later repressing Ato by inducing E(spl) bHLHs. N signaling balances these 26 opposing functions by directing its obligate nuclear transcription factor, Suppressor of Hairless 27 (Su(H)), only in repressing 5'-ato. In this study, we reveal a novel and more nuanced role for 28 Su(H) in its regulation of 5'-ato. During retinal patterning, Su(H) is required for the expression 29 Anterior open (Aop), which, in turn, promotes 5'-ato activity. We demonstrate that Aop is 30 induced early in retinal patterning via N pathway activity, wherein Aop is required cell-31 autonomously for robust Ato expression during photoreceptor specification. In aop mutants, 32 expression from both ato enhancers is perturbed, suggesting that Aop promotes the Ato 33 autoregulation through maintenance of ato-3' activity. Clonal analysis indicates that Aop 34 indirectly opposes E(spl)-mediated repression of Ato. In the absence of both Aop and E(spl), 35 Ato expression is restored and the founding ommatidial photoreceptors, R8s, are specified. 36 These findings suggest that N signaling, through a potentially conserved relationship with Aop, 37 imposes a delay on ato repression, thus permitting autoregulation and retinogenesis. 38 3 39 Author Summary: 40The eye of the fruit fly has served as a paradigm to understand tissue patterning.41 Complex intercellular signaling networks cooperate during retinal development to allow cells to 42 become specialized visual-system precursor neurons at a specific time and place. These 43 neurons are precisely spaced within the developing retina and later recruit other cells to form 44 the repeated units that comprise insect eyes. The exact placement of each precursor cell 45 precipitates from the precise regulation of the atonal gene, which is first expressed in a cluster 46 of (10-20) cells before becoming restricted to only one cell from each cluster. The Notch 47 signaling pathway is required for both aspects of atonal regulation, first permitting up-regulation 48 within each cluster, and then the subsequent down-regulation to a single cell. However, the 49 connection between these two modes of Notch signaling had remained unclear. In this report, 50 we have identified that the anterior open gene is required to impose a delay on the restrictive 51 mode of Notch signaling, permitting the initial up-regulation of atonal to occur freely. In flies 52 mutant for anterior open, atonal bypasses its own up-regulation and proceeds directly to its 53 singled-out pattern but with significantly diminished robustness than occurs normally.

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“…In WT, E(spl) are expressed dynamically across the MF (Fig. 8A; Baker et al, 1996; Majot and Bidwai, 2017). In aop clones, E(spl) immunolabeling resembles WT (Fig.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DrosophilaAop imposes a delay on E(spl)-mediated repression of Ato during R8 specification

et al. 2019

Preprint

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Protein kinase CK2 phosphorylates a conserved motif in the Notch effector E(spl)-Mγ

Jozwick

Bidwai²

2022

Mol Cell Biochem

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Across metazoans, the effects of Notch signaling are mediated via the Enhancer of Split (E(spl)/HES) basic Helix-Loop-Helix-Orange (bHLH-O) repressors. Although conserved, sequence diversity is, in large part, restricted to the C-terminal domain (CtD), which separates the O-domain from the penultimate WRPW motif that binds the co-repressor Groucho. While the kinases CK2 and MAPK target the CtD and regulate Drosophila E(spl)-M8 and mammalian HES6, the generality of this regulation to other E(spl)/HES repressors has remained unknown. To determine the broader impact of phosphorylation on this large family of repressors, we conducted bioinformatics, evolutionary and biochemical analyses. Our studies identify E(spl)-Mγ as a new target of native CK2 puri ed from Drosophila embryos, reveal that phosphorylation is speci c to CK2 and independent of the regulatory CK2-β subunit, and identify that the site of phosphorylation is juxtaposed to the WRPW motif, a feature unique to and conserved in the Mγ homologues over 50x10 6 years of Drosophila evolution. Thus, a preponderance of E(spl) homologues in Drosophila are targets for CK2, and the distinct positioning of the CK2 and MAPK sites, raises the prospect that phosphorylation underlies functional diversity of bHLH-O proteins.

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Analysis of transient hypermorphic activity of E(spl)D during R8 specification

Cited by 2 publications

References 56 publications

DrosophilaAop imposes a delay on E(spl)-mediated repression of Ato during R8 specification

DrosophilaAop imposes a delay on E(spl)-mediated repression of Ato during R8 specification

Protein kinase CK2 phosphorylates a conserved motif in the Notch effector E(spl)-Mγ

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