Systems Properties and Spatiotemporal Regulation of Cell Position Variability during Embryogenesis

Li, Xiaoyü; Zhao, Zhiguang; Xu, Weina; Fan, Rong; Xiao, Long; Ma, Xuehua; Du, Zhuo

doi:10.1016/j.celrep.2018.12.052

Cited by 27 publications

(42 citation statements)

References 38 publications

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“…Given the early onset of CEH-43 expression, we generated a loss of function allele to test whether it regulates early cell fate specification, and found that ceh-43 mutant allele homozygotes died as embryos ( Figure S4I), identical to that reported in a putative null allele (tm480) of ceh-43 (Doitsidou et al, 2013). As significant defects in fate specification and differentiation usually affect the 3D position of embryonic cells (Schnabel et al, 2006), we systematically quantified cell position phenotypes in ceh-43 mutant embryos using an established method (Li et al, 2019) ( Figure 5F). Indeed, the relative 3D positions of many early embryonic cells differed significantly from wild-type ( Figure 5F and Table S6); furthermore, the vast majority of affected cells were CEH-43-expressing cells or their descendants ( Figure 5G).…”

Section: Ceh-43 Specifically Regulates the Fates And Positions Of Celmentioning

confidence: 52%

Single-Cell Protein Atlas of Transcription Factors Reveals the Combinatorial Code for Spatiotemporal Patterning theC. elegansEmbryo

Zhao

Xiao

et al. 2020

Preprint

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SUMMARYA high-resolution protein atlas is essential for understanding the molecular basis of biological processes. Using protein-fusion reporters and imaging-based single-cell analyses, we present a protein expression atlas of C. elegans embryogenesis encompassing 266 transcription factors (TFs) in nearly all (90%) lineage-resolved cells. Single-cell analysis reveals a combinatorial code and cascade that elucidate the regulatory hierarchy between a large number of lineage-, tissue-, and time-specific TFs in spatiotemporal fate patterning. Guided by expression, we identify essential functions of CEH-43/DLX, a lineage-specific TF, and ELT-1/GATA3, a well-known skin fate specifier, in neuronal specification; and M03D4.4 as a pan-muscle TF in converging muscle differentiation in the body wall and pharynx. Finally, systems-level analysis of TF regulatory state uncovers lineage- and time-specific kinetics of fate progression and widespread detours of the trajectories of cell differentiation. Collectively, our work reveals a single-cell molecular atlas and general principles underlying the spatiotemporal patterning of a metazoan embryo.

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Section: Ceh-43 Specifically Regulates the Fates And Positions Of Celmentioning

confidence: 52%

Single-Cell Protein Atlas of Transcription Factors Reveals the Combinatorial Code for Spatiotemporal Patterning theC. elegansEmbryo

Zhao

Xiao

et al. 2020

Preprint

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“…Though reproducibility and variability of morphogenesis have been previously studied [1,23,31] , underlying mechanism still remains unclear due to lack of enough quantitative information from wild-type statistics and mutant phenotypic analysis. So far, with cell positions from 222 wild-type embryos normalized, a precise and reproducible 4D cell-arrangement pattern was reconstructed ( Fig.1G).…”

Section: Establishment Of Wild-type Morphogenesis Reference With Spatmentioning

confidence: 99%

System-Level Quantification and Phenotyping of Early Embryonic Morphogenesis ofCaenorhabditis elegans

Guan

Wong

et al. 2019

Preprint

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Cell lineage consists of cell division timing, cell migration and cell fate, and is highly conserved during development of nematode species. An outstanding question is how differentiated cells are genetically and physically regulated in order to migrate to their precise destination among individuals. Here, we first generated a reference embryo using time-lapse 3 dimensional images of 222 wild-type C. elegans embryos at about 1.5-minute interval. This was achieved by automatic tracing and quantitative analysis of cellular phenotypes from 4-to 24-cell stage, including cell cycle duration, division orientation and migration trajectory. We next characterized cell division timing and cell kinematic state, which suggests that eight groups of cells can be clustered based on invariant and distinct division sequence. Cells may still be moving while others start to divide, indicating strong robustness against motional noise in developing embryo. We then devised a system-level phenotyping method for detecting mutant defect in global growth rate, cell cycle duration, division orientation and cell arrangement. A total of 758 genes were selected for perturbation by RNA interference followed by automatic phenotyping, which suggests a cryptic genetic architecture coordinating early morphogenesis spatially and temporally. The high-quality wild-type reference supports a conceptual close-packing model for cell arrangement during 4-to 8-cell stage, implying fundamental mechanical laws regulating the topological structure of early C. elegans embryo. Also, we observed a series of remarkable morphogenesis phenomena such as induced defect or recovery from defect in mutant embryo. To facilitate use of this quantification system, we built a software named STAR 1.0 for visualizing the wild-type reference and mutant phenotype. It also allows automatic phenotyping of new mutant embryo. Taken together, we not only provide a statistical wild-type reference with defined variability, but also shed light on both genetic and physical mechanisms coordinating early embryonic morphogenesis of C. elegans. The statistical reference permits a sensitive approach for mutant phenotype analysis, with which we phenotype a total of 1818 mutant embryos by depletion of 758 genes. Figure 1. Establishment of wild-type morphogenesis reference with spatio-temporal properties at single-cell level. A. A pipeline consisting of data acquisition, quality control, data processing and data integration. B. Time-lapse 3D in vivo imaging, embryo reconstruction and automatic cell-position tracing on a C. elegans embryoexpressing GFP in nucleus (green) and PH(PLC1d1) in membrane (red). The whole duration lasted from 4-to 350-cell stage ; the membrane marker here is only for illustration purpose, as most of the data in this work was not obtained from this strain ; 2-cell, 4-cell and 8-cell stages are presented (Supplementary Material 2). C. Cell-lineage tree up to 51-cell stage with tissue-differentiation information [1,21] and cell grouping based on invariant division ordering...

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“…In fact, for the majority of mutants, variability in morphological phenotypes between individual cells in an isogenic cell population is likely not driven solely by a genotype‐to‐phenotype relationship, but rather by a combination of smaller contributions from various effects that impact single cells differently depending on their physiological state. A deeper understanding of this variability may also have broad medical implications and should provide insight into the variable penetrance of genes affecting developmental programs and disease genes (Cooper et al , ; Kammenga, ; Li et al , ; Xavier da Silveira Dos Santos & Liberali, ).…”

Section: Discussionmentioning

confidence: 99%

Systematic genetics and single‐cell imaging reveal widespread morphological pleiotropy and cell‐to‐cell variability

Ušaj

Sahin

Friesen

et al. 2020

Molecular Systems Biology

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Our ability to understand the genotype‐to‐phenotype relationship is hindered by the lack of detailed understanding of phenotypes at a single‐cell level. To systematically assess cell‐to‐cell phenotypic variability, we combined automated yeast genetics, high‐content screening and neural network‐based image analysis of single cells, focussing on genes that influence the architecture of four subcellular compartments of the endocytic pathway as a model system. Our unbiased assessment of the morphology of these compartments—endocytic patch, actin patch, late endosome and vacuole—identified 17 distinct mutant phenotypes associated with ~1,600 genes (~30% of all yeast genes). Approximately half of these mutants exhibited multiple phenotypes, highlighting the extent of morphological pleiotropy. Quantitative analysis also revealed that incomplete penetrance was prevalent, with the majority of mutants exhibiting substantial variability in phenotype at the single‐cell level. Our single‐cell analysis enabled exploration of factors that contribute to incomplete penetrance and cellular heterogeneity, including replicative age, organelle inheritance and response to stress.

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Systems Properties and Spatiotemporal Regulation of Cell Position Variability during Embryogenesis

Cited by 27 publications

References 38 publications

Single-Cell Protein Atlas of Transcription Factors Reveals the Combinatorial Code for Spatiotemporal Patterning theC. elegansEmbryo

Single-Cell Protein Atlas of Transcription Factors Reveals the Combinatorial Code for Spatiotemporal Patterning theC. elegansEmbryo

System-Level Quantification and Phenotyping of Early Embryonic Morphogenesis ofCaenorhabditis elegans

Systematic genetics and single‐cell imaging reveal widespread morphological pleiotropy and cell‐to‐cell variability

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