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A mex3 homolog is required for differentiation during planarian stem cell lineage development

ABSTRACT: Neoblasts are adult stem cells (ASCs) in planarians which sustain cell replacement during homeostasis and regeneration of any missing tissue. While numerous studies have examined genes underlying neoblast pluripotency, molecular pathways driving the postmitotic fate remain poorly defined. Here we used transcriptional profiling of irradiation-sensitive and -insensitive cell populations and RNA interference (RNAi) functional screening to uncover markers and regulators of postmitotic progeny. We identified 32 new markers, which distinguish two epithelial progenitor populations, and a planarian homolog to the MEX3 RNA-binding protein (Smed-mex3-1) as a key regulator of lineage progression. mex3-1 is required for generating progenitors of epithelial, neural, eye, pharyngeal, and protonephridial lineages, and restricting expansion of the stem cell compartment. We also demonstrate the utility of using mex3-1(RNAi) animals to identify additional progenitor markers. These results show that mex3-1 promotes differentiation in multiple, if not all, lineages, and maintains the balance between ASC self-renewal and commitment.

ORGANISM(S): Schmidtea mediterranea

PROVIDER: GSE68581 | GEO | 2015/06/15

SECONDARY ACCESSION(S): PRJNA283132

REPOSITORIES: GEO

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A mex3 homolog is required for differentiation during planarian stem cell lineage development

Project description:Neoblasts are adult stem cells (ASCs) in planarians which sustain cell replacement during homeostasis and regeneration of any missing tissue. While numerous studies have examined genes underlying neoblast pluripotency, molecular pathways driving the postmitotic fate remain poorly defined. Here we used transcriptional profiling of irradiation-sensitive and -insensitive cell populations and RNA interference (RNAi) functional screening to uncover markers and regulators of postmitotic progeny. We identified 32 new markers, which distinguish two epithelial progenitor populations, and a planarian homolog to the MEX3 RNA-binding protein (Smed-mex3-1) as a key regulator of lineage progression. mex3-1 is required for generating progenitors of epithelial, neural, eye, pharyngeal, and protonephridial lineages, and restricting expansion of the stem cell compartment. We also demonstrate the utility of using mex3-1(RNAi) animals to identify additional progenitor markers. These results show that mex3-1 promotes differentiation in multiple, if not all, lineages, and maintains the balance between ASC self-renewal and commitment. Sorted and irradiated animals were collected as previously described (Labbe, et al., 2012) and RNAi conditions were triplicated, RNA was purified independently, then each replicate was pooled in equal amounts for sequencing at the timepoint: 1 feed day 12 for control RNAi and mex3-1 RNAi.

2015-06-15 | E-GEOD-68581 | biostudies-arrayexpress

Egf signaling directs neoblast repopulation by regulating asymmetric cell division in planarians

Project description:The goal of this experiment is to identify target genes of Egf signaling which regulate recovery of the neoblast population following exposure to a sublethal dose of radiation. A large population of highly proliferative stem cells (neoblasts) is required for physiological tissue homeostasis and regeneration after injury in planarians. Recent studies indicate that survival of a few neoblasts after sublethal irradiation results in the clonal expansion of the surviving stem cells and the eventual restoration of tissue homeostasis and regenerative capacity. Many genes are known to be required for the normal function of neoblasts, but the precise mechanisms regulating the population dynamics of these adult pluripotent stem cells remain largely unknown. By coupling RNAi screening and sublethal irradiation, we uncovered a central role for Epidermal Growth Factor (EGF) signaling during in vivo neoblast expansion mediated by Smed-egfr-3 (egfr-3) and its putative ligand Smed-neuregulin-7 (nrg-7). Furthermore, the EGFR-3 protein localizes asymmetrically on the cytoplasmic membrane of neoblasts and the ratio of asymmetric to symmetric cell divisions decreases significantly in egfr-3(RNAi) worms. Our results not only provide the first molecular evidence of asymmetric stem cell divisions in planarian, but also demonstrate that EGF signaling likely functions as an essential regulator of neoblast clonal expansion.

2016-08-18 | GSE84025 | GEO

High throughput expression-based phenotyping and RNAi screening reveals novel regulators of planarian stem cells

Project description:The complexity of cell types and states revealed by scRNAseq cell atlases presents a challenge for the systematic analysis of fate determinants using traditional screening methodologies. Differentiation in the planarian Schmidtea mediterranea exemplifies this problem, as these animals continuously produce over 100 differentiated cell types for homeostasis and regeneration using adult pluripotent stem cells termed neoblasts. The signaling factors enabling neoblast self-renewal and selective differentiation of these many fates are still incompletely understood. We developed a method using high-throughput expression profiling by qPCR and whole-animal RNAseq to simultaneously assess numerous cell fate markers as the phenotypic readout in large-scale RNAi screens. Applying this method, we performed an RNAi screen of 400 kinases, receptors, and other regulatory molecules to reveal specific functions for 30 previously unknown factors in neoblast biology. 17 genes were required for neoblast maintenance, including factors likely involved in cell-cycle regulation, nutrient sensing, and chromatin modification. Multidimensional expression information additionally revealed several specific regulators of other neoblast activities, including a mink1 kinase regulating global neoblast differentiation, the energy responsive kinase adenylate kinase-2 regulating intestine specification within the neoblast population, an RNA acetyl transferase nat10 regulating epidermal differentiation, and a pak1 kinase that restricts neoblast localization to prevent tissue outgrowths. These results identify several new regulators of neoblast activities and demonstrate the applicability of expression-based screening for systematic analysis of stem cell phenotypes in whole animals.

2023-08-31 | GSE212136 | GEO

RNA Seq analysis of Schmidtea mediterranea treated with RNAi against chd4, p53, or unc22 to identify factors involved in neoblast differentiation.

Project description:Adult stem cells are tissue-specific cells with the capacity to self-renew and differentiate to continually replace cells lost to normal physiological turnover or injury. Neoblasts, the planarian stem cells, are widely distributed throughout the body mesenchyme, driving constitutive renewal of tissues during homeostasis and endowing planarians with the remarkable capacity to regenerate wholly from tiny tissue fragments. Neoblasts are the only dividing cells in planarians and are believed to be collectively comprised of both a heterogeneous population of pluripotent cells with broad differentiation potential and also lineage-committed progenitor cells that give rise to specific tissues. Recent work has identified a prominent class of neoblasts referred to as zeta-class, which express the zinc-finger gene zfp-1. Zfp-1, along with the chromatin remodeling factor chd4, the tumor suppressor gene p53, and most recently an RNA-binding protein mex3-1, have all been shown to be required for maintenance of two related post-mitotic, sub-epidermal cell populations expressing the specific marker genes prog-1 and AGAT-1, which have been widely used to asses neoblast differentiation. Given that zeta-class neoblasts are required for the generation of prog-1 and AGAT-1 positive cells and other markers of epidermal cell types, prog-1 and AGAT-1 likely mark two major populations of epidermal progeny cells. To understand the molecular mechanisms underlying neoblast differentiation and how they give rise to multiple cell types, we devised a strategy to identify critical factors enriched in the AGAT-1 positive cell population required for epidermal lineage progression. We performed RNA-Seq analysis of chd4 and p53 RNAi animals and characterized additional markers enriched in AGAT-1 positive and related post-mitotic cells.

2015-10-21 | GSE72389 | GEO

Identification of TOR-responsive slow-cycling neoblasts in planarians

Project description:Epimorphic regeneration commonly relies on the activation of quiescent stem cells to drive new cell production. The planarian Schmidtea mediterranea is among the best regenerators in nature, thanks to its large population of adult stem cells, called neoblasts. While neoblasts have long been known to drive regeneration, whether a subset of neoblasts is reserved for this purpose is unknown. Here, we revisited the idea of reserved neoblasts by approaching neoblast heterogeneity from a regulatory perspective. By implementing a new fluorescence-activated cell sorting strategy in planarians, we identified a population of neoblasts defined by low transcriptional activity. These RNAlow neoblasts are relatively slow-cycling at homeostasis and undergo a morphological regeneration response characterized by cell growth at 48 hours post-amputation. At this time, RNAlow neoblasts proliferated in a TOR-dependent manner. Additionally, knockdown of the tumour suppressor Lrig-1, which is enriched in RNAlow neoblasts, resulted in RNAlow neoblast growth and hyperproliferation at homeostasis, and ultimately delayed regeneration. We propose that slow-cycling RNAlow neoblasts represent a regeneration-reserved neoblast population.

2020-12-31 | GSE157860 | GEO

454 Life Sciences/Roche and Illumina sequencing of small RNAs from planarian samples

Project description:Freshwater planarian flatworms possess uncanny regenerative capacities mediated by abundant and collectively totipotent adult stem cells. Key functions of these cells during regeneration and tissue homeostasis have been shown to depend on PIWI, a molecule required for piRNA expression in planarians. Nevertheless, the full complement of piRNAs, and microRNAs (miRNAs) in this organism has yet to be defined. Here, we report on the large scale cloning and sequencing of small RNAs from the planarian Schmidtea mediterranea, yielding altogether millions of sequenced unique small RNAs. We show that piRNAs are in part organized in genomic clusters and that they share characteristic features with mammalian and fly piRNAs. We further identify 61 novel miRNA genes and thus double the number of known planarian miRNAs. Sequencing, as well as quantitative PCR of small RNAs uncovered ten miRNAs enriched in planarian stem cells. These miRNAs are down-regulated in animals in which stem cells have been abrogated by irradiation, and thus constitute miRNAs likely associated with specific stem cell functions. Altogether, we present the first comprehensive small RNA analysis in animals belonging to the third animal superphylum, the Lophotrochozoa, and single out a number of miRNAs that may function in regeneration. Several of these miRNAs are deeply conserved in animals. Small RNAs were sequenced from FACS-sorted neoblast stem cells, untreated planarians and irradiated planarians, depleted of neoblasts

2009-06-30 | E-GEOD-16159 | biostudies-arrayexpress

RNA Seq analysis of sorted Schmidtea mediterranea X1 and Xins cells to identify factors specific to neoblasts

2015-12-17 | E-GEOD-73027 | biostudies-arrayexpress

Planarian stem cells

Project description:Difficulty of experimental accessing makes in vivo stem cell studies not easy in mammals and model systems with regenerative capability represent an alternative for the characterization of stem cell-specific genes. Planarians retain a population of pluripotent stem cells, the neoblasts, throughout their adult life. Neoblasts can be selectively destroyed by X-ray allowing us to compare stem cell-less organisms with wild-type worms. We have undertaken a genomic approach producing an Keywords: X-ray, dose response, stem cells, stress response

2006-07-19 | GSE5318 | GEO

A tetraspanin family member functionally resolves and facilitates the purification of adult pluripotent stem cells used for whole-body regeneration (Bulk)

Project description:Proliferating cells known as neoblasts include pluripotent stem cells (PSCs) capable of sustaining tissue homeostasis and regeneration of lost body parts in planarians. However, the lack of markers to prospectively identify and isolate these adult PSCs has significantly hampered their characterization. We used single-cell RNA sequencing (scRNA-seq) and single cell transplantation to address this long-standing issue. Large-scale scRNA-seq of fluorescently sorted neoblasts unveiled a novel subtype of neoblast (Nb2) characterized by high levels of PIWI-1 mRNA and protein, and marked by a conserved cell-surface protein coding gene, tetraspanin 1 (tspan1). tspan1-positive cells survived sub-lethal irradiation, underwent clonal expansion to repopulate whole animals, and when purified with an anti-TSPAN-1 antibody rescued with high efficiency the viability of lethally irradiated animals after single-cell transplantation. Our work demonstrates the first prospective isolation of an adult PSC, bridges a conceptual dichotomy between operationally and molecularly defined neoblasts, and sheds light on the mechanisms governing in vivo pluripotency and the source of regeneration in planarians.

2018-06-14 | GSE107874 | GEO

Tetraspanin family member functionally resolves and facilitates the purification of adult pluripotent stem cells used for whole-body regeneration (Single)

2018-06-14 | GSE107873 | GEO

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