Phenotypic Robustness of Epidermal Stem Cell Number in C. elegans Is Modulated by the Activity of the Conserved N-acetyltransferase nath-10/NAT10

Individual cells and organisms experience perturbations from internal and external sources, yet manage to buffer these to produce consistent phenotypes, a property known as robustness. While phenotypic robustness has often been examined in unicellular organisms, it has not been sufficiently studied in multicellular animals. Here, we investigate phenotypic robustness in Caenorhabditis elegans seam cells. Seam cells are stem cell-like epithelial cells along the lateral edges of the animal, which go through asymmetric and symmetric divisions contributing cells to the hypodermis and neurons, while replenishing the stem cell reservoir. The terminal number of seam cells is almost invariant in the wild-type population, allowing the investigation of how developmental precision is achieved. We report here that a loss-of-function mutation in the highly conserved N-acetyltransferase nath-10/NAT10 increases seam cell number variance in the isogenic population. RNA-seq analysis revealed increased levels of mRNA transcript variability in nath-10 mutant populations, which may have an impact on the phenotypic variability observed. Furthermore, we found disruption of Wnt signaling upon perturbing nath-10 function, as evidenced by changes in POP-1/TCF nuclear distribution and ectopic activation of its GATA transcription factor target egl-18. These results highlight that NATH-10/NAT-10 can influence phenotypic variability partly through modulation of the Wnt signaling pathway.

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Faculty Opinions recommendation of Phenotypic Robustness of Epidermal Stem Cell Number in C. elegans Is Modulated by the Activity of the Conserved N-acetyltransferase nath-10/NAT10.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.740235842.793586652 ◽

2021 ◽

Author(s):

Helen Chamberlin

Keyword(s):

Stem Cell ◽

Cell Number ◽

Epidermal Stem Cell ◽

C Elegans ◽

Phenotypic Robustness

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Faculty Opinions recommendation of Wnt signaling and CEH-22/tinman/Nkx2.5 specify a stem cell niche in C. elegans.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1012242.373077 ◽

2006 ◽

Author(s):

Michael Herman

Keyword(s):

Stem Cell ◽

Wnt Signaling ◽

Stem Cell Niche ◽

C Elegans ◽

Cell Niche

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A role for the fusogen eff-1 in epidermal stem cell number robustness in Caenorhabditis elegans

Scientific Reports ◽

10.1038/s41598-021-88500-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sneha L. Koneru ◽

Fu Xiang Quah ◽

Ritobrata Ghose ◽

Mark Hintze ◽

Nicola Gritti ◽

...

Keyword(s):

Stem Cell ◽

Caenorhabditis Elegans ◽

Cell Fate ◽

Single Molecule ◽

Phenotypic Variability ◽

Low Frequency ◽

Time Lapse ◽

Cell Number ◽

Seam Cell ◽

Neuronal Tissues

AbstractDevelopmental patterning in Caenorhabditis elegans is known to proceed in a highly stereotypical manner, which raises the question of how developmental robustness is achieved despite the inevitable stochastic noise. We focus here on a population of epidermal cells, the seam cells, which show stem cell-like behaviour and divide symmetrically and asymmetrically over post-embryonic development to generate epidermal and neuronal tissues. We have conducted a mutagenesis screen to identify mutants that introduce phenotypic variability in the normally invariant seam cell population. We report here that a null mutation in the fusogen eff-1 increases seam cell number variability. Using time-lapse microscopy and single molecule fluorescence hybridisation, we find that seam cell division and differentiation patterns are mostly unperturbed in eff-1 mutants, indicating that cell fusion is uncoupled from the cell differentiation programme. Nevertheless, seam cell losses due to the inappropriate differentiation of both daughter cells following division, as well as seam cell gains through symmetric divisions towards the seam cell fate were observed at low frequency. We show that these stochastic errors likely arise through accumulation of defects interrupting the continuity of the seam and changing seam cell shape, highlighting the role of tissue homeostasis in suppressing phenotypic variability during development.

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A Wnt signaling pathway controls hox gene expression and neuroblast migration in C. elegans

Development ◽

10.1242/dev.126.1.37 ◽

1999 ◽

Vol 126 (1) ◽

pp. 37-49 ◽

Cited By ~ 9

Author(s):

J.N. Maloof ◽

J. Whangbo ◽

J.M. Harris ◽

G.D. Jongeward ◽

C. Kenyon

Keyword(s):

Gene Expression ◽

Wnt Signaling ◽

Wnt Pathway ◽

Hox Genes ◽

Wnt Signaling Pathway ◽

Beta Catenin ◽

Hox Gene ◽

C Elegans ◽

Neuroblast Migration ◽

Pathway Gene

The specification of body pattern along the anteroposterior (A/P) body axis is achieved largely by the actions of conserved clusters of Hox genes. Limiting expression of these genes to localized regional domains and controlling the precise patterns of expression within those domains is critically important for normal patterning. Here we report that egl-20, a C. elegans gene required to activate expression of the Hox gene mab-5 in the migratory neuroblast QL, encodes a member of the Wnt family of secreted glycoproteins. We have found that a second Wnt pathway gene, bar-1, which encodes a beta-catenin/Armadillo-like protein, is also required for activation of mab-5 expression in QL. In addition, we describe the gene pry-1, which is required to limit expression of the Hox genes lin-39, mab-5 and egl-5 to their correct local domains. We find that egl-20, pry-1 and bar-1 all function in a linear genetic pathway with conserved Wnt signaling components, suggesting that a conserved Wnt pathway activates expression of mab-5 in the migratory neuroblast QL. Moreover, we find that members of this Wnt signaling system play a major role in both the general and fine-scale control of Hox gene expression in other cell types along the A/P axis.

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The stem-loop binding protein CDL-1 is required for chromosome condensation, progression of cell death and morphogenesis inCaenorhabditis elegans

Development ◽

10.1242/dev.129.1.187 ◽

2002 ◽

Vol 129 (1) ◽

pp. 187-196 ◽

Cited By ~ 1

Author(s):

Yuki Kodama ◽

Joel H. Rothman ◽

Asako Sugimoto ◽

Masayuki Yamamoto

Keyword(s):

Cell Death ◽

Structural Changes ◽

Binding Protein ◽

Core Histone ◽

Loss Of Function ◽

Histone Proteins ◽

Stem Loop ◽

C Elegans ◽

Morphological Defects ◽

In The Wild

Histones play important roles not only in the structural changes of chromatin but also in regulating gene expression. Expression of histones is partly regulated post-transcriptionally by the stem-loop binding protein (SLBP)/hairpin binding protein (HBP). We report the developmental function of CDL-1, the C. elegans homologue of SLBP/HBP. In the C. elegans cdl-1 mutants, cell corpses resulting from programmed cell death appear later and persist much longer than those in the wild type. They also exhibit distinct morphological defects in body elongation and movement of the pharyngeal cells toward the buccal opening. The CDL-1 protein binds to the stem-loop structures in the 3′-UTR of C. elegans core histone mRNAs, and the mutant forms of this protein show reduced binding activities. A decrease in the amount of core histone proteins phenocopied the cdl-1 mutant embryos, suggesting that CDL-1 contributes to the proper expression of core histone proteins. We propose that loss-of-function of cdl-1 causes aberrant chromatin structure, which affects the cell cycle and cell death, as well as transcription of genes essential for morphogenesis.

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Silencing of long noncoding RNA HOXA11-AS inhibits the Wnt signaling pathway via the upregulation of HOXA11 and thereby inhibits the proliferation, invasion, and self-renewal of hepatocellular carcinoma stem cells

Experimental & Molecular Medicine ◽

10.1038/s12276-019-0328-x ◽

2019 ◽

Vol 51 (11) ◽

pp. 1-20 ◽

Cited By ~ 2

Author(s):

Jun-Cheng Guo ◽

Yi-Jun Yang ◽

Jin-Fang Zheng ◽

Jian-Quan Zhang ◽

Min Guo ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Stem Cells ◽

Stem Cell ◽

Wnt Signaling ◽

Signaling Pathway ◽

Methylation Level ◽

Wnt Signaling Pathway ◽

The Self ◽

Self Renewal

AbstractHepatocellular carcinoma (HCC) is a major cause of cancer-related deaths, but its molecular mechanisms are not yet well characterized. Long noncoding RNAs (lncRNAs) play crucial roles in tumorigenesis, including that of HCC. However, the role of homeobox A11 antisense (HOXA11-AS) in determining HCC stem cell characteristics remains to be explained; hence, this study aimed to investigate the effects of HOXA11-AS on HCC stem cell characteristics. Initially, the expression patterns of HOXA11-AS and HOXA11 in HCC tissues, cells, and stem cells were determined. HCC stem cells, successfully sorted from Hep3B and Huh7 cells, were transfected with short hairpin or overexpression plasmids for HOXA11-AS or HOXA11 overexpression and depletion, with an aim to study the influences of these mediators on the self-renewal, proliferation, migration, and tumorigenicity of HCC stem cells in vivo. Additionally, the potential relationship and the regulatory mechanisms that link HOXA11-AS, HOXA11, and the Wnt signaling pathway were explored through treatment with Dickkopf-1 (a Wnt signaling pathway inhibitor). HCC stem cells showed high expression of HOXA11-AS and low expression of HOXA11. Both HOXA11-AS silencing and HOXA11 overexpression suppressed the self-renewal, proliferation, migration, and tumorigenicity of HCC stem cells in vivo, as evidenced by the decreased expression of cancer stem cell surface markers (CD133 and CD44) and stemness-related transcription factors (Nanog, Sox2, and Oct4). Moreover, silencing HOXA11-AS inactivated the Wnt signaling pathway by decreasing the methylation level of the HOXA11 promoter, thereby inhibiting HCC stem cell characteristics. Collectively, this study suggested that HOXA11-AS silencing exerts an antitumor effect, suppressing HCC development via Wnt signaling pathway inactivation by decreasing the methylation level of the HOXA11 promoter.

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