Outstanding questions in developmental ERK signaling

Patel, Aleena L.; Shvartsman, Stanislav Y.

doi:10.1242/dev.143818

Cited by 52 publications

(49 citation statements)

References 132 publications

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“…In many organisms, the epidermal growth factor receptors (EGFR), one of families of the receptor tyrosine kinases (RTK), are known to regulate several biological processes by activating key downstream pathways including the MAPK pathway [26][27][28][29][43][44][45] . In planarians, Smed-egfr-3 is required for proper regeneration as well as for ERK activation (Fig.4) 24,46 .…”

Section: Discussionmentioning

confidence: 99%

“…Literature has already described examples of the activation of EGFR signaling by ROS and the potential of EGFR in mediating MAPK signaling including ERK activation [24][25][26][27][28][29][30][31] . Additionally, the egr (early growth response) family of transcription factors is suggested to be a downstream target of EGFR signaling in planarian regeneration as well as in other models [32][33][34][35] .…”

Section: Smed-egfr-3 and Smed-egr-4 Silencing Impair Ros Production Amentioning

confidence: 99%

“…Many studies already indicated an interplay between ROS and mitogenactivated protein kinases (MAPK) signaling pathways [18][19][20][21][22] 24,25 and other models [26][27][28][29] . Also, the activation of the EGFR pathway by ROS has been described in different models 30,31 .…”

Section: Introductionmentioning

confidence: 99%

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Hydrogen peroxide as regeneration-initiation signal that activates pERK to trigger planarian regeneration

Jaenen

Fraguas

Bijnens

et al. 2019

Preprint

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Despite the extensive research on molecular pathways controlling the process of regeneration in planarians and other regeneration models, little is known about the actual initiation signals necessary to induce regeneration. Previously the involvement of ROS, EGFR and MAPK/ERK has been demonstrated during planarian regeneration, however the exact interplay has not been yet described. By selectively interfering with major mediators in all three key parts (ROS, EGFR & MAPK/ERK), we were able to identify amputation/wound-induced ROS, and H 2 O 2 specifically, as upstream cue in activating regeneration-initiation. In addition, our results demonstrate new relationships between regeneration related ROS production and MAPK/ERK activation at early regeneration stages, as well as the involvement of the EGFR-signaling pathway. In summary, our results suggest a new and more extensive signaling model with ROS, and H 2 O 2 , highlighted as upstream initiationfactor and its important functions in the downstream EGFR-MAPK/ERK pathway during planarian regeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Smed-egfr-3 and Smed-egr-4 Silencing Impair Ros Production Amentioning

confidence: 99%

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Hydrogen peroxide as regeneration-initiation signal that activates pERK to trigger planarian regeneration

Jaenen

Fraguas

Bijnens

et al. 2019

Preprint

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“…The mitogen activated protein (MAP) kinase pathway drives proliferation and differentiation during development and regeneration in many organisms (Ghilardi et al, 2020;Patel & Shvartsman, 2018). In planarians, the MAP kinase ERK is the earliest known signal required for regeneration.…”

Section: Erk Phosphorylation Is Required For Increased Pharyngeal Promentioning

confidence: 99%

Planarian stem cells sense the identity of missing tissues to launch targeted regeneration

Bohr

Shiroor

Adler

2020

Preprint

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In order to regenerate tissues successfully, stem cells must first detect injuries and then produce missing cell types through largely unknown mechanisms. Planarian flatworms have an extensive stem cell population responsible for regenerating any organ after amputation. Here, we compare stem cell responses to different injuries by amputation of a single organ, the pharynx, or removal of tissues from other organs by decapitation. We find that planarian stem cells adopt distinct behaviors depending on what tissue is missing: loss of non-pharyngeal tissues increases numbers of non-pharyngeal progenitors, while removal of the pharynx specifically triggers proliferation and expansion of pharynx progenitors. By pharmacologically inhibiting either proliferation or activation of the MAP kinase ERK, we identify a narrow window of time during which proliferation, followed by ERK signaling, produces pharynx progenitors necessary for regeneration. Further, unlike pharynx regeneration, eye regeneration does not depend on proliferation or ERK activation. These results indicate that stem cells tailor their proliferation and expansion to match the regenerative needs of the animal.

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“…Activation of this cascade then initiates further downstream signaling, often through activation of downstream transcription factors 1 . Dysregulation of the Ras/MAPK pathway is well established to derail a host of biological phenotypes 2 .…”

Section: Introductionmentioning

confidence: 99%

Exploiting codon usage identifies RpS21 as anin vivosignal strength-dependent Ras/MAPK regulator

Sawyer

Kabiri

Montague

et al. 2019

Preprint

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Accumulating evidence suggests the evolutionarily conserved Ras/mitogen activated protein kinase (MAPK) signaling pathway directs distinct biological consequences that depend on distinct intensity states. Given this intensity-dependence, we hypothesized that different levels of Ras/MAPK signaling may be subjected to regulation by different sets of proteins. To identify such 'differential' signaling modifiers, we turned to the Drosophila eye as a model. First, we created flies whereby mutant active Ras V12 expressed in the eyes was enriched with either rare or commonly occurring codons. We show that this codon manipulation can generate either low or high levels of Ras protein and MAPK signaling, and correspondingly a mild or severe rough-eye phenotype. Using this novel platform to control Ras/MAPK signaling, we performed a wholegenome haploinsufficiency deficiency screen, which yielded 15 deficiencies that modify the rougheye phenotype in either high or low MAPK signaling states, but not both. We then mapped the underlying gene from one deficiency to the gene RpS21. Disrupting RpS21 expression increases MAPK signaling and enhances the rough-eye phenotype specifically when Ras V12 is encoded by rare codons (low signaling), and RpS21 negatively regulates Ras protein and MAPK signaling in several contexts. We also provide evidence that the MAPK pathway promotes expression of RpS21, providing potential negative feedback. Taken together, these data reveal intensityspecific regulation of Ras/MAPK signaling, with the first candidate of this class being RpS21.

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Outstanding questions in developmental ERK signaling

Cited by 52 publications

References 132 publications

Hydrogen peroxide as regeneration-initiation signal that activates pERK to trigger planarian regeneration

Hydrogen peroxide as regeneration-initiation signal that activates pERK to trigger planarian regeneration

Planarian stem cells sense the identity of missing tissues to launch targeted regeneration

Exploiting codon usage identifies RpS21 as anin vivosignal strength-dependent Ras/MAPK regulator

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