New Publications Citing SmedGD

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A premeiotic function for boule in the planarian Schmidtea mediterranea

Iyer H, Issigonis M, Sharma PP, Extavour CG, Newmark PA Proc. Natl. Acad. Sci. U.S.A. 2016 Jun;113(25):E3509-18 PMID: 27330085 Abstract Mutations in Deleted in Azoospermia (DAZ), a Y chromosome gene,

NF-YB Regulates Spermatogonial Stem Cell Self-Renewal and Proliferation in the Planarian Schmidtea mediterranea

Iyer H, Collins JJ, Newmark PA PLoS Genet. 2016 Jun;12(6):e1006109 PMID: 27304889 Abstract Gametes are the source and carrier of genetic information, essential for the propagation of all sexually reproducing

Regional signals in the planarian body guide stem cell fate in the presence of genomic instability

Peiris TH, Ramirez D, Barghouth PG, Ofoha U, Davidian D, Weckerle F, Oviedo NJ Development 2016 May;143(10):1697-709 PMID: 27013241 Abstract Cellular fate decisions are influenced by their topographical location in

GPCRs Direct Germline Development and Somatic Gonad Function in Planarians

Saberi A, Jamal A, Beets I, Schoofs L, Newmark PA PLoS Biol. 2016 May;14(5):e1002457 PMID: 27163480 Abstract Planarians display remarkable plasticity in maintenance of their germline, with the ability to

A prefoldin-associated WD-repeat protein (WDR92) is required for the correct architectural assembly of motile cilia

Patel-King RS, King SM Mol. Biol. Cell 2016 Apr;27(8):1204-9 PMID: 26912790 Abstract WDR92 is a highly conserved WD-repeat protein that has been proposed to be involved in apoptosis and also

A premeiotic function for boule in the planarian Schmidtea mediterranea

Iyer H, Issigonis M, Sharma PP, Extavour CG, Newmark PA

Proc. Natl. Acad. Sci. U.S.A. 2016 Jun;113(25):E3509-18

PMID: 27330085

Abstract

Mutations in Deleted in Azoospermia (DAZ), a Y chromosome gene, are an important cause of human male infertility. DAZ is found exclusively in primates, limiting functional studies of this gene to its homologs: boule, required for meiotic progression of germ cells in invertebrate model systems, and Daz-like (Dazl), required for early germ cell maintenance in vertebrates. Dazl is believed to have acquired its premeiotic role in a vertebrate ancestor following the duplication and functional divergence of the single-copy gene boule. However, multiple homologs of boule have been identified in some invertebrates, raising the possibility that some of these genes may play other roles, including a premeiotic function. Here we identify two boule paralogs in the freshwater planarian Schmidtea mediterranea Smed-boule1 is necessary for meiotic progression of male germ cells, similar to the known function of boule in invertebrates. By contrast, Smed-boule2 is required for the maintenance of early male germ cells, similar to vertebrate Dazl To examine if Boule2 may be functionally similar to vertebrate Dazl, we identify and functionally characterize planarian homologs of human DAZL/DAZ-interacting partners and DAZ family mRNA targets. Finally, our phylogenetic analyses indicate that premeiotic functions of planarian boule2 and vertebrate Dazl evolved independently. Our study uncovers a premeiotic role for an invertebrate boule homolog and offers a tractable invertebrate model system for studying the premeiotic functions of the DAZ protein family.

NF-YB Regulates Spermatogonial Stem Cell Self-Renewal and Proliferation in the Planarian Schmidtea mediterranea

Iyer H, Collins JJ, Newmark PA

PLoS Genet. 2016 Jun;12(6):e1006109

PMID: 27304889

Abstract

Gametes are the source and carrier of genetic information, essential for the propagation of all sexually reproducing organisms. Male gametes are derived from a progenitor stem cell population called spermatogonial stem cells (SSCs). SSCs give rise to male gametes through the coordination of two essential processes: self-renewal to produce more SSCs, and differentiation to produce mature sperm. Disruption of this equilibrium can lead to excessive proliferation of SSCs, causing tumorigenesis, or can result in aberrant differentiation, leading to infertility. Little is known about how SSCs achieve the fine balance between self-renewal and differentiation, which is necessary for their remarkable output and developmental potential. To understand the mechanisms of SSC maintenance, we examine the planarian homolog of Nuclear Factor Y-B (NF-YB), which is required for the maintenance of early planarian male germ cells. Here, we demonstrate that NF-YB plays a role in the self-renewal and proliferation of planarian SSCs, but not in their specification or differentiation. Furthermore, we characterize members of the NF-Y complex in Schistosoma mansoni, a parasitic flatworm related to the free-living planarian. We find that the function of NF-YB in regulating male germ cell proliferation is conserved in schistosomes. This finding is especially significant because fecundity is the cause of pathogenesis of S. mansoni. Our findings can help elucidate the complex relationship between self-renewal and differentiation of SSCs, and may also have implications for understanding and controlling schistosomiasis.

Regional signals in the planarian body guide stem cell fate in the presence of genomic instability

Peiris TH, Ramirez D, Barghouth PG, Ofoha U, Davidian D, Weckerle F, Oviedo NJ

Development 2016 May;143(10):1697-709

PMID: 27013241

Abstract

Cellular fate decisions are influenced by their topographical location in the adult body. For instance, tissue repair and neoplastic growth are greater in anterior than in posterior regions of adult animals. However, the molecular underpinnings of these regional differences are unknown. We identified a regional switch in the adult planarian body upon systemic disruption of homologous recombination with RNA-interference of Rad51 Rad51 knockdown increases DNA double-strand breaks (DSBs) throughout the body, but stem cells react differently depending on their location along the anteroposterior axis. In the presence of extensive DSBs, cells in the anterior part of the body resist death, whereas cells in the posterior region undergo apoptosis. Furthermore, we found that proliferation of cells with DNA damage is induced in the presence of brain tissue and that the retinoblastoma pathway enables overproliferation of cells with DSBs while attending to the demands of tissue growth and repair. Our results implicate both autonomous and non-autonomous mechanisms as key mediators of regional cell behavior and cellular transformation in the adult body.

GPCRs Direct Germline Development and Somatic Gonad Function in Planarians

Saberi A, Jamal A, Beets I, Schoofs L, Newmark PA

PLoS Biol. 2016 May;14(5):e1002457

PMID: 27163480

Abstract

Planarians display remarkable plasticity in maintenance of their germline, with the ability to develop or dismantle reproductive tissues in response to systemic and environmental cues. Here, we investigated the role of G protein-coupled receptors (GPCRs) in this dynamic germline regulation. By genome-enabled receptor mining, we identified 566 putative planarian GPCRs and classified them into conserved and phylum-specific subfamilies. We performed a functional screen to identify NPYR-1 as the cognate receptor for NPY-8, a neuropeptide required for sexual maturation and germ cell differentiation. Similar to NPY-8, knockdown of this receptor results in loss of differentiated germ cells and sexual maturity. NPYR-1 is expressed in neuroendocrine cells of the central nervous system and can be activated specifically by NPY-8 in cell-based assays. Additionally, we screened the complement of GPCRs with expression enriched in sexually reproducing planarians, and identified an orphan chemoreceptor family member, ophis, that controls differentiation of germline stem cells (GSCs). ophis is expressed in somatic cells of male and female gonads, as well as in accessory reproductive tissues. We have previously shown that somatic gonadal cells are required for male GSC specification and maintenance in planarians. However, ophis is not essential for GSC specification or maintenance and, therefore, defines a secondary role for planarian gonadal niche cells in promoting GSC differentiation. Our studies uncover the complement of planarian GPCRs and reveal previously unappreciated roles for these receptors in systemic and local (i.e., niche) regulation of germ cell development.

A prefoldin-associated WD-repeat protein (WDR92) is required for the correct architectural assembly of motile cilia

Patel-King RS, King SM

Mol. Biol. Cell 2016 Apr;27(8):1204-9

PMID: 26912790

Abstract

WDR92 is a highly conserved WD-repeat protein that has been proposed to be involved in apoptosis and also to be part of a prefoldin-like cochaperone complex. We found that WDR92 has a phylogenetic signature that is generally compatible with it playing a role in the assembly or function of specifically motile cilia. To test this hypothesis, we performed an RNAi-based knockdown of WDR92 gene expression in the planarianSchmidtea mediterraneaand were able to achieve a robust reduction in mRNA expression to levels undetectable under our standard RT-PCR conditions. We found that this treatment resulted in a dramatic reduction in the rate of organismal movement that was caused by a switch in the mode of locomotion from smooth, cilia-driven gliding to muscle-based, peristaltic contractions. Although the knockdown animals still assembled cilia of normal length and in similar numbers to controls, these structures had reduced beat frequency and did not maintain hydrodynamic coupling. By transmission electron microscopy we observed that many cilia had pleiomorphic defects in their architecture, including partial loss of dynein arms, incomplete closure of the B-tubule, and occlusion or replacement of the central pair complex by accumulated electron-dense material. These observations suggest that WDR92 is part of a previously unrecognized cytoplasmic chaperone system that is specifically required to fold key components necessary to build motile ciliary axonemes.

Planarian brain regeneration as a model system for developmental neurotoxicology

Hagstrom D, Cochet-Escartin O, Collins EM

Regeneration (Oxf) 2016 Apr;3(2):65-77

PMID: 27499880

Abstract

Freshwater planarians, famous for their regenerative prowess, have long been recognized as a valuable in vivo animal model to study the effects of chemical exposure. In this review, we summarize the current techniques and tools used in the literature to assess toxicity in the planarian system. We focus on the planarian’s particular amenability for neurotoxicology and neuroregeneration studies, owing to the planarian’s unique ability to regenerate a centralized nervous system. Zooming in from the organismal to the molecular level, we show that planarians offer a repertoire of morphological and behavioral readouts while also being amenable to mechanistic studies of compound toxicity. Finally, we discuss the open challenges and opportunities for planarian brain regeneration to become an important model system for modern toxicology.

Evolution of the EGFR pathway in Metazoa and its diversification in the planarian Schmidtea mediterranea

Barberán S, Martín-Durán JM, Cebrià F

Sci Rep 2016;6:28071

PMID: 27325311

Abstract

The EGFR pathway is an essential signaling system in animals, whose core components are the epidermal growth factors (EGF ligands) and their trans-membrane tyrosine kinase receptors (EGFRs). Despite extensive knowledge in classical model organisms, little is known of the composition and function of the EGFR pathway in most animal lineages. Here, we have performed an extensive search for the presence of EGFRs and EGF ligands in representative species of most major animal clades, with special focus on the planarian Schmidtea mediterranea. With the exception of placozoans and cnidarians, we found that the EGFR pathway is potentially present in all other analyzed animal groups, and has experienced frequent independent expansions. We further characterized the expression domains of the EGFR/EGF identified in S. mediterranea, revealing a wide variety of patterns and localization in almost all planarian tissues. Finally, functional experiments suggest an interaction between one of the previously described receptors, Smed-egfr-5, and the newly found ligand Smed-egf-6. Our findings provide the most comprehensive overview to date of the EGFR pathway, and indicate that the last common metazoan ancestor had an initial complement of one EGFR and one putative EGF ligand, which was often expanded or lost during animal evolution.

Light-induced depigmentation in planarians models the pathophysiology of acute porphyrias

Stubenhaus BM, Dustin JP, Neverett ER, Beaudry MS, Nadeau LE, Burk-McCoy E, He X, Pearson BJ, Pellettieri J

Elife 2016;5

PMID: 27240733

Abstract

Porphyrias are disorders of heme metabolism frequently characterized by extreme photosensitivity. This symptom results from accumulation of porphyrins, tetrapyrrole intermediates in heme biosynthesis that generate reactive oxygen species when exposed to light, in the skin of affected individuals. Here we report that in addition to producing an ommochrome body pigment, the planarian flatworm Schmidtea mediterranea generates porphyrins in its subepithelial pigment cells under physiological conditions, and that this leads to pigment cell loss when animals are exposed to intense visible light. Remarkably, porphyrin biosynthesis and light-induced depigmentation are enhanced by starvation, recapitulating a common feature of some porphyrias – decreased nutrient intake precipitates an acute manifestation of the disease. Our results establish planarians as an experimentally tractable animal model for research into the pathophysiology of acute porphyrias, and potentially for the identification of novel pharmacological interventions capable of alleviating porphyrin-mediated photosensitivity or decoupling dieting and fasting from disease pathogenesis.

Wnt, Ptk7, and FGFRL expression gradients control trunk positional identity in planarian regeneration

Lander R, Petersen CP

Elife 2016;5

PMID: 27074666

Abstract

Mechanisms enabling positional identity re-establishment are likely critical for tissue regeneration. Planarians use Wnt/beta-catenin signaling to polarize the termini of their anteroposterior axis, but little is known about how regeneration signaling restores regionalization along body or organ axes. We identify three genes expressed constitutively in overlapping body-wide transcriptional gradients that control trunk-tail positional identity in regeneration. ptk7 encodes a trunk-expressed kinase-dead Wnt co-receptor, wntP-2 encodes a posterior-expressed Wnt ligand, and ndl-3 encodes an anterior-expressed homolog of conserved FGFRL/nou-darake decoy receptors. ptk7 and wntP-2 maintain and allow appropriate regeneration of trunk tissue position independently of canonical Wnt signaling and with suppression of ndl-3 expression in the posterior. These results suggest that restoration of regional identity in regeneration involves the interpretation and re-establishment of axis-wide transcriptional gradients of signaling molecules.

HOX gene complement and expression in the planarian Schmidtea mediterranea

Currie KW, Brown DD, Zhu S, Xu C, Voisin V, Bader GD, Pearson BJ

Evodevo 2016;7:7

PMID: 27034770

Abstract

BACKGROUND: Freshwater planarians are well known for their regenerative abilities. Less well known is how planarians maintain spatial patterning in long-lived adult animals or how they re-pattern tissues during regeneration. HOX genes are good candidates to regulate planarian spatial patterning, yet the full complement or genomic clustering of planarian HOX genes has not yet been described, primarily because only a few have been detectable by in situ hybridization, and none have given morphological phenotypes when knocked down by RNAi.

RESULTS: Because the planarian Schmidtea mediterranea (S. mediterranea) is unsegmented, appendage less, and morphologically simple, it has been proposed that it may have a simplified HOX gene complement. Here, we argue against this hypothesis and show that S. mediterranea has a total of 13 HOX genes, which represent homologs to all major axial categories, and can be detected by whole-mount in situ hybridization using a highly sensitive method. In addition, we show that planarian HOX genes do not cluster in the genome, yet 5/13 have retained aspects of axially restricted expression. Finally, we confirm HOX gene axial expression by RNA deep-sequencing 6 anterior-posterior “zones” of the animal, which we provide as a dataset to the community to discover other axially restricted transcripts.

CONCLUSIONS: Freshwater planarians have an unappreciated HOX gene complexity, with all major axial categories represented. However, we conclude based on adult expression patterns that planarians have a derived body plan and their asexual lifestyle may have allowed for large changes in HOX expression from the last common ancestor between arthropods, flatworms, and vertebrates. Using our in situ method and axial zone RNAseq data, it should be possible to further understand the pathways that pattern the anterior-posterior axis of adult planarians.