Enhancers of glp-1, a gene required for cell-signaling in Caenorhabditis elegans, define a set of genes required for germline development.

Qiao, Li; Lissemore, James L.; Shu, Pei; Smardon, Anne M.; Gelber, Melanie B.; Maine, Eleanor M.

doi:10.1093/genetics/141.2.551

Cited by 82 publications

(17 citation statements)

References 33 publications

(16 reference statements)

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“…We next analysed odr-1/guanylate cyclase effector gene expression in AWB neurons, the sister cell of ADF, and found similar odr-1/guanylate cyclase expression in lag-1(q385) mutant and wild-type animals (S2 Fig) . Altogether, these results suggest that LAG-1 function is dispensable for the generation of 2 neurons in the terminal branch of the ADF lineage (ADF and AWB neurons) or for ADF neuron survival, but it is necessary for correct ADF neuron terminal differentiation, likely through direct activation of ADF expressed effector genes. Similar broad ADF expression defects are found in the thermosensitive hypomorphic allele lag-1(om13), although the phenotype is observed only when worms are grown at 15˚C and only transiently during L1 (S2 Fig) . This allele shows slight germline and somatic defects, which are stronger at 20 to 25˚C compared to 15˚C [15]. The transient phenotype we observe is likely due to the weak nature of this hypomorphic allele in which enough LAG-1 activity in the ADF neuron might be reached either at longer times or at higher temperatures.…”

Section: Plos Biologymentioning

confidence: 75%

The transcription factor LAG-1/CSL plays a Notch-independent role in controlling terminal differentiation, fate maintenance, and plasticity of serotonergic chemosensory neurons

et al. 2021

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During development, signal-regulated transcription factors (TFs) act as basal repressors and upon signalling through morphogens or cell-to-cell signalling shift to activators, mediating precise and transient responses. Conversely, at the final steps of neuron specification, terminal selector TFs directly initiate and maintain neuron-type specific gene expression through enduring functions as activators. C. elegans contains 3 types of serotonin synthesising neurons that share the expression of the serotonin biosynthesis pathway genes but not of other effector genes. Here, we find an unconventional role for LAG-1, the signal-regulated TF mediator of the Notch pathway, as terminal selector for the ADF serotonergic chemosensory neuron, but not for other serotonergic neuron types. Regulatory regions of ADF effector genes contain functional LAG-1 binding sites that mediate activation but not basal repression. lag-1 mutants show broad defects in ADF effector genes activation, and LAG-1 is required to maintain ADF cell fate and functions throughout life. Unexpectedly, contrary to reported basal repression state for LAG-1 prior to Notch receptor activation, gene expression activation in the ADF neuron by LAG-1 does not require Notch signalling, demonstrating a default activator state for LAG-1 independent of Notch. We hypothesise that the enduring activity of terminal selectors on target genes required uncoupling LAG-1 activating role from receiving the transient Notch signalling.

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Section: Plos Biologymentioning

confidence: 75%

The transcription factor LAG-1/CSL plays a Notch-independent role in controlling terminal differentiation, fate maintenance, and plasticity of serotonergic chemosensory neurons

et al. 2021

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“…We found that at 20°C, cup-2(0); glp-1(bn18) gonads have ~95 cells in the proliferative zone, while cup-2(0) and glp-1(bn18) have ~195 and ~138, respectively ( Fig 2B ) ( Table 2 ). While it does appear that cup-2(0) enhances the smaller proliferative zone phenotype of glp-1(bn18) , we do not consider this to be a strong enhancement because enhancement is not to the point of causing a Glp (germ line proliferation defective) phenotype in which no proliferative cells are present [ 30 ], which is observed with other enhancers of glp-1(bn18) [ 64 ]. Even at 22.5°C we do not observe enhancement resulting in Glp animals ( S2 Table ).…”

Section: Resultsmentioning

confidence: 99%

Reduction of Derlin activity suppresses Notch-dependent tumours in the C. elegans germ line

et al. 2021

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Regulating the balance between self-renewal (proliferation) and differentiation is key to the long-term functioning of all stem cell pools. In the Caenorhabditis elegans germline, the primary signal controlling this balance is the conserved Notch signaling pathway. Gain-of-function mutations in the GLP-1/Notch receptor cause increased stem cell self-renewal, resulting in a tumor of proliferating germline stem cells. Notch gain-of-function mutations activate the receptor, even in the presence of little or no ligand, and have been associated with many human diseases, including cancers. We demonstrate that reduction in CUP-2 and DER-2 function, which are Derlin family proteins that function in endoplasmic reticulum-associated degradation (ERAD), suppresses the C. elegans germline over-proliferation phenotype associated with glp-1(gain-of-function) mutations. We further demonstrate that their reduction does not suppress other mutations that cause over-proliferation, suggesting that over-proliferation suppression due to loss of Derlin activity is specific to glp-1/Notch (gain-of-function) mutations. Reduction of CUP-2 Derlin activity reduces the expression of a read-out of GLP-1/Notch signaling, suggesting that the suppression of over-proliferation in Derlin loss-of-function mutants is due to a reduction in the activity of the mutated GLP-1/Notch(GF) receptor. Over-proliferation suppression in cup-2 mutants is only seen when the Unfolded Protein Response (UPR) is functioning properly, suggesting that the suppression, and reduction in GLP-1/Notch signaling levels, observed in Derlin mutants may be the result of activation of the UPR. Chemically inducing ER stress also suppress glp-1(gf) over-proliferation but not other mutations that cause over-proliferation. Therefore, ER stress and activation of the UPR may help correct for increased GLP-1/Notch signaling levels, and associated over-proliferation, in the C. elegans germline.

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“…We found that at 20°C, cup-2(0); glp-1(bn18) gonads have ~95 cells in the proliferative zone, while cup-2(0) and glp-1(bn18) have ~195 and ~138, respectively (Fig 2B ) (Table 2). While it does appear that cup-2(0) enhances the smaller proliferative zone phenotype of glp-1(bn18), we do not consider this to be a strong enhancement because enhancement is not to the point of causing a Glp (germ line proliferation defective) phenotype in which no proliferative cells are present (27), which is observed with other enhancers of glp-1(bn18) (57). Even at 22.5°C we do not observe enhancement resulting in Glp animals (Supp Table 1).…”

Section: Loss Of Cup-2 Suppress Glp-1(gf) Tumours In Correlation With the Strength Of Glp-1/notch Signallingmentioning

confidence: 90%

Reduction of Derlin activity suppresses Notch-dependent tumours in the C. elegans germ line

Singh

Smit

Wang

et al. 2021

Preprint

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Regulating the balance between self-renewal (proliferation) and differentiation is key to the long-term functioning of all stem cell pools. In the Caenorhabditis elegans germline, the primary signal controlling this balance is the conserved Notch signaling pathway. Gain-of-function mutations in the GLP-1/Notch receptor cause increased stem cell self-renewal, resulting in a tumor of proliferating germline stem cells. Notch gain-of-function mutations activate the receptor, even in the presence of little or no ligand, and have been associated with many human diseases, including cancers. We demonstrate that reduction in CUP-2 and DER-2 function, which are Derlin family proteins that function in endoplasmic-reticulum-associated degradation (ERAD), suppresses the C. elegans germline over-proliferation phenotype associated with glp-1(gain-of-function) mutations. We further demonstrate that their reduction does not suppress other mutations that cause over-proliferation, suggesting that over-proliferation suppression due to loss of Derlin activity is specific to glp-1/Notch (gain-of-function) mutations. Reduction of CUP-2 Derlin activity reduces the expression of a read-out of GLP-1/Notch signaling, suggesting that the suppression of over-proliferation in Derlin loss-of-function mutants is due to a reduction in the activity of the mutated GLP-1/Notch(GF) receptor. Over-proliferation suppression in cup-2 mutants is only seen when the Unfolded Protein Response (UPR) is functioning properly, suggesting that the suppression, and reduction in GLP-1/Notch signaling levels, observed in Derlin mutants may be the result of activation of the UPR. Chemically inducing ER stress also suppress glp-1(gf) over-proliferation but not other mutations that cause over-proliferation. Therefore, ER stress and activation of the UPR may help correct for increased GLP-1/Notch signaling levels, and associated over-proliferation, in the C. elegans germline.

show abstract

Enhancers of glp-1, a gene required for cell-signaling in Caenorhabditis elegans, define a set of genes required for germline development.

Cited by 82 publications

References 33 publications

The transcription factor LAG-1/CSL plays a Notch-independent role in controlling terminal differentiation, fate maintenance, and plasticity of serotonergic chemosensory neurons

The transcription factor LAG-1/CSL plays a Notch-independent role in controlling terminal differentiation, fate maintenance, and plasticity of serotonergic chemosensory neurons

Reduction of Derlin activity suppresses Notch-dependent tumours in the C. elegans germ line

Reduction of Derlin activity suppresses Notch-dependent tumours in the C. elegans germ line

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