Drosophila hedgehog can act as a morphogen in the absence of regulated Ci processing

Little, Jamie C; Garcia-Garcia, Elisa; Sul, Amanda; Kalderon, Daniel

doi:10.7554/elife.61083

Cited by 9 publications

(4 citation statements)

References 73 publications

(155 reference statements)

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“…To test definitively whether Ci155 is responsible for accelerating the furrow in emc clones, we generated emc ci double mutant clones. To achieve this, a genomic transgene that rescues ci 94 flies to adulthood (Little, Garcia-Garcia, Sul, & Kalderon, 2020), was introduced into chromosome arm 3L where it is linked to the wild type emc locus, so that mitotic recombination in the ci 94 null background leads to emc ci double mutant clones. For unknown reasons, emc ci double mutant clones were small and difficult to obtain, even in the Minute background.…”

Section: Resultsmentioning

confidence: 99%

Extramacrochaetae regulates Notch signaling in theDrosophilaeye through non-apoptotic caspase activity

Nair,

Baker

2023

Preprint

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Many cell fate decisions are determined transcriptionally. Accordingly, some fate specification is prevented by Inhibitor of DNA binding (Id) proteins that interfere with certain master regulatory transcription factors. We report that theDrosophilaId protein Extra macrochaetae (Emc) also affects developmental decisions by regulating caspase activity. Emc, which prevents proneural bHLH transcription factors from specifying neural cell fate, also prevents homodimerization of another bHLH protein, Daughterless (Da), and thereby maintains expression of theDeath-Associated Inhibitor of Apoptosis(diap1) gene. Multiple effects ofemcmutations, on cell growth and on eye development, were all caused by reduced Diap1 levels and corresponding activation of caspases. These effects included growth of unspecified imaginal disc cells, acceleration of the morphogenetic furrow, failure of R7 photoreceptor cell specification, and delayed differentiation of non-neuronal cone cells. Withinemcmutant eye clones, morphogenetic furrow speed was increased by elevated Notch signaling, while decreased Notch signaling inhibited R7 specification and cone cell differentiation. This was all due to caspase-dependent increase in levels of Delta protein, a transmembrane ligand that both trans- activates and cis-inhibits Notch. Thus,emcmutations reveal the importance of restraining caspase activity, even in non-apoptotic cells, to prevent abnormal development.

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Section: Resultsmentioning

confidence: 99%

Extramacrochaetae regulates Notch signaling in theDrosophilaeye through non-apoptotic caspase activity

Nair,

Baker

2023

Preprint

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“…We noticed that Ci -PKA_SD123 was still activated by CC-Fu EE and Hh ( Figs 2E and F and 3E’ ), suggesting that additional mechanisms regulated by Hh/Fu may contribute to Ci/Gli activation. For example, Hh signaling could activate Ci by releasing the inhibition of full-length Ci by PKA and Cos2 independent of Ci processing ( Price & Kalderon, 1999 ; Wang et al, 1999 ; Little et al, 2020 ). Hh signaling could induce Ci phosphorylation by CK1 on multiple HIB/SPOP degrons to protect Ci A from premature degradation by Cul3 HIB/SPOP ( Zhang et al, 2006 ; Shi et al, 2014b ).…”

Section: Discussionmentioning

confidence: 99%

Dose-dependent phosphorylation and activation of Hh pathway transcription factors

et al. 2022

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Graded Hedgehog (Hh) signaling is mediated by graded Cubitus interruptus (Ci)/Gli transcriptional activity, but how the Hh gradient is converted into the Ci/Gli activity gradient remains poorly understood. Here, we show that graded Hh induces a progressive increase in Ci phosphorylation at multiple Fused (Fu)/CK1 sites including a cluster located in the C-terminal Sufu-binding domain. We demonstrated that Fu directly phosphorylated Ci on S1382, priming CK1 phosphorylation on adjacent sites, and that Fu/CK1-mediated phosphorylation of the C-terminal sites interfered with Sufu binding and facilitated Ci activation. Phosphorylation at the N-terminal, middle, and C-terminal Fu/CK1 sites occurred independently of one another and each increased progressively in response to increasing levels of Hh or increasing amounts of Hh exposure time. Increasing the number of phospho-mimetic mutations of Fu/CK1 sites resulted in progressively increased Ci activation by alleviating Sufu-mediated inhibition. We found that the C-terminal Fu/CK1 phosphorylation cluster is conserved in Gli2 and contributes to its dose-dependent activation. Our study suggests that the Hh signaling gradient is translated into a Ci/Gli phosphorylation gradient that activates Ci/Gli by gradually releasing Sufu-mediated inhibition.

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“…An early study suggested that PKA not only regulates the production of Ci R but also inhibits Ci A because blockage of Ci R production by slimb mutation in Drosophila wing imaginal discs only resulted in ectopic expression of decapentaplegic (dpp), a Hh target gene normally inhibited by Ci R ; however, inactivation of PKA not only resulted in ectopic expression of dpp but also ptc, which is normally activated by Ci A (Jiang and Struhl, 1998;Methot and Basler, 1999;Wang et al, 1999). Furthermore, processing-deficient forms of Ci is still inhibited by PKA (Wang et al, 1999;Marks and Kalderon, 2011;Little et al, 2020). In addition to phosphorylating the three phosphorylation clusters in the C-terminal half of Ci, PKA also phosphorylates two additional sites in the C-terminal half of Ci (Figure 2).…”

Section: Processing-independent Inhibition Of Ci/gli By Pkamentioning

confidence: 99%

Gli Phosphorylation Code in Hedgehog Signal Transduction

Zhou

Jen

2022

Front. Cell Dev. Biol.

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Hedgehog (Hh) family of secreted proteins governs many key processes in embryonic development and adult tissue homeostasis in species ranging from insects to human. Deregulation of Hh signaling has been implicated in a wide range of human diseases including birth defect and cancer. Hh signaling pathway culminates in the conversion of the latent transcription factor Cubitus interruptus (Ci)/Gli from a repressor form (CiR/GliR) into an activator form (CiA/GliA). Both the production of CiR/GliR in the absence of Hh and the formation of CiA/GliA in response to Hh are regulated by phosphorylation. Whereas previous studies demonstrated that sequential phosphorylation by protein kinase A (PKA), glycogen synthase kinase 3 (GSK3), and casein kinase 1 (CK1) at multiple Ser/Thr clusters in the C-terminal region of Ci/Gli targets it for proteolytic processing to generate CiR/GliR, recent studies revealed that phosphorylation of Ci/Gli by the Fused (Fu)/Unc-51 like kinase (Ulk) family kinases Fu/Ulk3/Stk36 and other kinases contributes to Ci/Gli activation. Fu/Ulk3/Stk36-mediated phosphorylation of Ci/Gli is stimulated by Hh, leading to altered interaction between Ci/Gli and the Hh pathway repressor Sufu. Here we review our current understanding of how various Ci/Gli phosphorylation events are regulated and how they influence Hh signal transduction.

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Drosophila hedgehog can act as a morphogen in the absence of regulated Ci processing

Cited by 9 publications

References 73 publications

Extramacrochaetae regulates Notch signaling in theDrosophilaeye through non-apoptotic caspase activity

Extramacrochaetae regulates Notch signaling in theDrosophilaeye through non-apoptotic caspase activity

Dose-dependent phosphorylation and activation of Hh pathway transcription factors

Gli Phosphorylation Code in Hedgehog Signal Transduction

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