The Signaling Network Controlling C. elegans Vulval Cell Fate Patterning

Shin, Hyun‐Tak; Reiner, David J.

doi:10.3390/jdb6040030

Cited by 24 publications

(15 citation statements)

References 178 publications

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“…The significance of this change is unclear, since many transcriptional fusions of vulval signaling genes change expression patterns around this time [5–7, 10, 12, 47, 48]; reviewed in [52]. One interpretation is that increased expression of RGL-1 in presumptive 1° cells accounts for resistance to rgl-1(RNAi) of this putative 1°-promoting activity of RGL-1.…”

Section: Resultsmentioning

confidence: 99%

“…A critical question, then, is how the programming of signal transduction networks decreases the potential for errors (developmental stochasticity or “noise”). Previously, the fidelity of VPC fate patterning was thought to be a property that emerges from the combination of three mechanisms: 1) sequential induction sets up the basic pattern, 2) graded signal collaborates with Sequential Induction to more precisely sculpt the initial pattern, and 3) mutual antagonism serves to exclude potentially conflicting signals from cells that are initially specified, thus preventing assumption of ambiguous fates (reviewed in [52]). We speculate that the roles we describe here for RGL-1 define a fourth method that is woven into the other three: orchestration of two modulatory cascades to more sharply demarcate fates as a function of the VPC’s spatial relationship to the AC and other VPCs.…”

Section: Discussionmentioning

confidence: 99%

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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%

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…We have also postulated the mutual antagonism model [ 21 ]. In response to initial patterning of VPC fates by the two core signaling cascades, Ras-Raf-MAP kinase and Notch, a series of additional signals and transcriptional changes in signaling molecules occur.…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, presumptive 2° cells express ERK LIP-1 phosphatase (DUSP or MAP kinase phosphatase “MKP” in Figure 1 ) as a Notch LIN-12 transcriptional client gene to quench inappropriate ERK MPK-1 activation in these cells, thus preventing conflicting 1°-promoting signals in VPCs that are assuming 2° fate [ 24 ]. A series of other regulatory events presumably contribute similarly to preventing contradictory signals, and thus are likely to increase the developmental fidelity of the system (reviewed in [ 21 ]).…”

Section: Introductionmentioning

confidence: 99%

Insulated Switches: Dual-Function Protein RalGEFRGL-1 Promotes Developmental Fidelity

Duong

Rasmussen

Reiner

2020

IJMS

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The C. elegans vulva is an excellent model for the study of developmental biology and cell–cell signaling. The developmental induction of vulval precursor cells (VPCs) to assume the 3°-3°-2°-1°-2°-3° patterning of cell fates occurs with 99.8% accuracy. During C. elegans vulval development, an EGF signal from the anchor cell initiates the activation of RasLET-60 > RafLIN-45 > MEKMEK-2 > ERKMPK-1 signaling cascade to induce the 1° cell. The presumptive 1° cell signals its two neighboring cells via NotchLIN-12 to develop 2° cells. In addition, RasLET-60 switches effectors to RalGEFRGL-1 > RalRAL-1 to promote 2° fate. Shin et al. (2019) showed that RalGEFRGL-1 is a dual-function protein in VPCs fate patterning. RalGEFRGL-1 functions as a scaffold for PDKPDK-1 > AktAKT-1/2 modulatory signaling to promote 1° fate in addition to propagating the RasLET-60 modulatory signal through RalRAL-1 to promote 2° fate. The deletion of RalGEFRGL-1 increases the frequency of VPC patterning errors 15-fold compared to the wild-type control. We speculate that RalGEFRGL-1 represents an “insulated switch”, whereby the promotion of one signaling activity curtails the promotion of the opposing activity. This property might increase the impact of the switch on fidelity more than two separately encoded proteins could. Understanding how developmental fidelity is controlled will help us to better understand the origins of cancer and birth defects, which occur in part due to the misspecification of cell fates.

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“…P4.p-P8.p always become vulval progenitors, while in 50% of animals, P3.p receives insufficient Wnt and adopts the non-progenitor 4°fate where it fuses with the hyp7 hypodermal syncytium without dividing (Eisenmann et al, 1998). Later, LIN-3 levels rise in the anchor cell and trigger vulval induction by stimulating LET-23/ EGFR in P6.p, the nearest progenitor (reviewed by Shin and Reiner, 2018). P6.p adopts the 1°fate and stimulates Notch in P5.p and P7.p, which cooperates with low levels of EGFR signaling to induce 2°fates in these cells.…”

Section: Introductionmentioning

confidence: 99%

Sensory regulated Wnt production from neurons helps make organ development robust to environmental changes in C. elegans

et al. 2020

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Long-term survival of an animal species depends on development being robust to environmental variations and climate changes. We used C. elegans to study how mechanisms that sense environmental changes trigger adaptive responses that ensure animals develop properly. In water, the nervous system induces an adaptive response that reinforces vulval development through an unknown backup signal for vulval induction. This response involves the heterotrimeric G-protein EGL-30//Gαq acting in motor neurons. It also requires body-wall muscle, which is excited by EGL-30-stimulated synaptic transmission, suggesting a behavioral function of neurons induces backup signal production from muscle. We now report that increased acetylcholine during liquid growth activates an EGL-30-Rho pathway, distinct from the synaptic transmission pathway, that increases Wnt production from motor neurons. We also provide evidence that this neuronal Wnt contributes to EGL-30-stimulated vulval development, with muscle producing a parallel developmental signal. As diverse sensory modalities stimulate motor neurons via acetylcholine, this mechanism enables broad sensory perception to enhance Wnt-dependent development. Thus, sensory perception improves animal fitness by activating distinct neuronal functions that trigger adaptive changes in both behavior and developmental processes.

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The Signaling Network Controlling C. elegans Vulval Cell Fate Patterning

Cited by 24 publications

References 178 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

Insulated Switches: Dual-Function Protein RalGEFRGL-1 Promotes Developmental Fidelity

Sensory regulated Wnt production from neurons helps make organ development robust to environmental changes in C. elegans

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