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Ruth Lehmann

Publications and source records attributed to Ruth Lehmann.

At least 19 recordsLinked to original sources
PubMed2006

The role of Tudor domains in germline development and polar granule architecture.

Tudor domains are found in many organisms and have been implicated in protein-protein interactions in which methylated protein substrates bind to these domains. Here, we present evidence for the involvement of specific Tudor domains in germline development. Drosophila Tudor, the founder of the Tudor domain family, contains 11 Tudor domains and is a component of polar granules and nuage, electron-dense organelles characteristic of the germline in many organisms, including mammals. In this study, we investigated whether the 11 Tudor domains fulfil specific functions for polar granule assembly, germ cell formation and abdomen formation. We find that even a small number of non-overlapping Tudor domains or a substantial reduction in overall Tudor protein is sufficient for abdomen development. In stark contrast, we find a requirement for specific Tudor domains in germ cell formation, Tudor localization and polar granule architecture. Combining genetic analysis with structural modeling of specific Tudor domains, we propose that these domains serve as ;docking platforms' for polar granule assembly.

Abdomen↗
PubMed2006

Soma-germline interactions coordinate homeostasis and growth in the Drosophila gonad.

The ability of organs such as the liver or the lymphoid system to maintain their original size or regain it after injury is well documented. However, little is known about how these organs sense that equilibrium is breached, and how they cease changing when homeostasis is reached. Similarly, it remains unclear how, during normal development, different cell types within an organ coordinate their growth. Here we show that during gonad development in the fruitfly Drosophila melanogaster the proliferation of primordial germ cells (PGCs) and survival of the somatic intermingled cells (ICs) that contact them are coordinated by means of a feedback mechanism composed of a positive signal and a negative signal. PGCs express the EGF receptor (EGFR) ligand Spitz, which is required for IC survival. In turn, ICs inhibit PGC proliferation. Thus, homeostasis and coordination of growth between soma and germ line in the larval ovary is achieved by using a sensor of PGC numbers (EGFR-mediated survival of ICs) coupled to a correction mechanism inhibiting PGC proliferation. This feedback loop ensures that sufficient numbers of PGCs exist to fill all the stem-cell niches that form at the end of larval development. We propose that similar feedback mechanisms might be generally used for coordinated growth, regeneration and homeostasis.

Animals↗
PubMed2006

Follow the fatty brick road: lipid signaling in cell migration.

Lysophospholipids play important roles in the migration of lymphocytes, smooth muscle cells and germ cells in vertebrates and invertebrates. In vertebrates, the migratory responses are mediated by specific G-protein-coupled receptors. These are expressed in both migrating lymphocyte and smooth muscle cells, and in their surrounding cells. In Drosophila germ cell migration, lipid phosphatases also act in both the surrounding and the migrating cells. In all three scenarios, the contributions of these genes in the stationary and migrating cells are being teased apart by genetic studies and direct observation, with exciting results.

Animals↗
PubMed2006

In vivo migration: a germ cell perspective.

The basic concepts of the molecular machinery that mediates cell migration have been gleaned from cell culture systems. However, the three-dimensional environment within an organism presents migrating cells with a much greater challenge. They must move between and among other cells while interpreting multiple attractive and repulsive cues to choose their proper path. They must coordinate their cell adhesion with their surroundings and know when to start and stop moving. New insights into the control of these remaining mysteries have emerged from genetic dissection and live imaging of germ cell migration in Drosophila, zebrafish, and mouse embryos. In this review, we first describe germ cell migration in cellular and mechanistic detail in these different model systems. We then compare these systems to highlight the emerging principles. Finally, we contrast the migration of germ cells with that of immune and cancer cells to outline the conserved and different mechanisms.

Animals↗
PubMed2006

Can quality of movement be measured? Rasch analysis and inter-rater reliability of the Motor Evaluation Scale for Upper Extremity in Stroke Patients (MESUPES).

OBJECTIVE: Clinical scales evaluating arm function after stroke are weak at detecting quality of movement. Therefore a new scale, the Motor Evaluation Scale for Upper Extremity in Stroke Patients (MESUPES), was developed, comprising 22 items pertaining to arm and hand performance. The scale was investigated for validity and unidimensionality using the Rasch measurement model, and for inter-rater reliability. SETTING: Twelve hospitals and rehabilitation centres in Belgium, Germany and Switzerland. PATIENTS: There were 396 patients (average age 63.38+/-12.89 years) in the Rasch study and 56 patients (average age 65.68+/-12.75 years) in the reliability study. MAIN MEASURES: The scale was examined on its fit to the Rasch model, thereby evaluating the scale's unidimensionality and validity. Differential item functioning was performed to test the stability of item hierarchy on several variables. Inter-rater reliability was examined with kappa values, weighted percentage agreement and intraclass correlation coefficients (ICC). RESULTS: Based on Rasch analysis, five items were removed. The MESUPES was divided in two tests: the MESUPES-arm test (8 items) and MESUPES-hand test (9 items). Both scales fitted the Rasch model. All items were stable among the subgroups of the sample. ICCs were 0.95 (95% confidence interval (CI) 0.91 -0.97) and 0.97 (95% CI 0.95-0.98) for the total score on arm and hand test respectively. The scale was also reliable at item level (weighted kappa 0.62 -0.79, weighted percentage agreement 85.71 -98.21). CONCLUSION: The MESUPES-arm and MESUPES-hand meet the statistical properties of reliability, validity and unidimensionality. Both tests provide a useful clinical and research tool to qualitatively evaluate arm and hand function during recovery after stroke.

Aged↗
PubMed2005

Control of lateral migration and germ cell elimination by the Drosophila melanogaster lipid phosphate phosphatases Wunen and Wunen 2.

In most organisms, primordial germ cells (PGCs) arise far from the region where somatic gonadal precursors (SGPs) are specified. Although PGCs in general originate as a single cluster of cells, the somatic parts of the gonad form on each site of the embryo. Thus, to reach the gonad, PGCs not only migrate from their site of origin but also split into two groups. Taking advantage of high-resolution real-time imaging, we show that in Drosophila melanogaster PGCs are polarized and migrate directionally toward the SGPs, avoiding the midline. Unexpectedly, neither PGC attractants synthesized in the SGPs nor known midline repellents for axon guidance were required to sort PGCs bilaterally. Repellent activity provided by wunen (wun) and wunen-2 (wun-2) expressed in the central nervous system, however, is essential in this migration process and controls PGC survival. Our results suggest that expression of wun/wun-2 repellents along the migratory paths provides faithful control over the sorting of PGCs into two gonads and eliminates PGCs left in the middle of the embryo.

Alleles↗
PubMed2005

twin, a CCR4 homolog, regulates cyclin poly(A) tail length to permit Drosophila oogenesis.

Cyclins regulate progression through the cell cycle. Control of cyclin levels is essential in Drosophila oogenesis for the four synchronous divisions that generate the 16 cell germ line cyst and for ensuring that one cell in each cyst, the oocyte, is arrested in meiosis, while the remaining fifteen cells become polyploid nurse cells. Changes in cyclin levels could be achieved by regulating transcription, translation or protein stability. The proteasome limits cyclin protein levels in the Drosophila ovary, but the mechanisms regulating RNA turnover or translation remain largely unclear. Here, we report the identification of twin, a homolog of the yeast CCR4 deadenylase. We show that twin is important for the number and synchrony of cyst divisions and oocyte fate. Consistent with the deadenylase activity of CCR4 in yeast, our data suggest that Twin controls germ line cyst development by regulating poly(A) tail lengths of several targets including Cyclin A (CycA) RNA. twin mutants exhibit very low expression of Bag-of-marbles (Bam), a regulator of cyst division, indicating that Twin/Ccr4 activity is necessary for wild-type Bam expression. Lowering the levels of CycA or increasing the levels of Bam suppresses the defects we observe in twin ovaries, implicating CycA and Bam as downstream effectors of Twin. We propose that Twin/Ccr4 functions during early oogenesis to coordinate cyst division, oocyte fate specification and egg chamber maturation.

Adenosine↗
PubMed2004

Germ cell specification and migration in Drosophila and beyond.

The passage of an individual's genome to future generations is essential for the maintenance of species and is mediated by highly specialized cells, the germ cells. Genetic studies in a number of model organisms have provided insight into the molecular mechanisms that control specification, migration and survival of early germ cells. Focusing on Drosophila, we will discuss the mechanisms by which germ cells initially form and remain transcriptionally silent while somatic cells are transcriptionally active. We will further discuss three separate attractive and repellent guidance pathways, mediated by a G-protein coupled receptor, two lipid phosphate phosphohydrolases, and isoprenylation. We will compare and contrast these findings with those obtained in other organisms, in particular zebrafish and mice. While aspects of germ cell specification are strikingly different between these species, germ cell specific gene functions have been conserved. In particular, mechanisms that sense directional cues during germ cell migration seem to be shared between invertebrates and vertebrates.

Animals↗
PubMed2004

Repression of primordial germ cell differentiation parallels germ line stem cell maintenance.

In Drosophila, primordial germ cells (PGCs) are set aside from somatic cells and subsequently migrate through the embryo and associate with somatic gonadal cells to form the embryonic gonad. During larval stages, PGCs proliferate in the female gonad, and a subset of PGCs are selected at late larval stages to become germ line stem cells (GSCs), the source of continuous egg production throughout adulthood. However, the degree of similarity between PGCs and the self-renewing GSCs is unclear. Here we show that many of the genes that are required for GSC maintenance in adults are also required to prevent precocious differentiation of PGCs within the larval ovary. We show that following overexpression of the GSC-differentiation gene bag of marbles (bam), PGCs differentiate to form cysts without becoming GSCs. Furthermore, PGCs that are mutant for nanos (nos), pumilio (pum) or for signaling components of the decapentaplegic (dpp) pathway also differentiate. The similarity in the genes necessary for GSC maintenance and the repression of PGC differentiation suggest that PGCs and GSCs may be functionally equivalent and that the larval gonad functions as a "PGC niche".

Animals↗
PubMed2004

Egalitarian binds dynein light chain to establish oocyte polarity and maintain oocyte fate.

In many cell types polarized transport directs the movement of mRNAs and proteins from their site of synthesis to their site of action, thus conferring cell polarity. The cytoplasmic dynein microtubule motor complex is involved in this process. In Drosophila melanogaster, the Egalitarian (Egl) and Bicaudal-D (BicD) proteins are also essential for the transport of macromolecules to the oocyte and to the apical surface of the blastoderm embryo. Hence, Egl and BicD, which have been shown to associate, may be part of a conserved core localization machinery in Drosophila, although a direct association between these molecules and the dynein motor complex has not been shown. Here we report that Egl interacts directly with Drosophila dynein light chain (Dlc), a microtubule motor component, through an Egl domain distinct from that which binds BicD. We propose that the Egl-BicD complex is loaded through Dlc onto the dynein motor complex thereby facilitating transport of cargo. Consistent with this model, point mutations that specifically disrupt Egl-Dlc association also disrupt microtubule-dependant trafficking both to and within the oocyte, resulting in a loss of oocyte fate maintenance and polarity. Our data provide a direct link between a molecule necessary for oocyte specification and the microtubule motor complex, and supports the hypothesis that microtubule-mediated transport is important for preserving oocyte fate.

Animals↗
PubMed2004

A noncoding RNA is required for the repression of RNApolII-dependent transcription in primordial germ cells.

RNApolII-dependent transcription is repressed in primordial germ cells of many animals during early development and is thought to be important for maintenance of germline fate by preventing somatic differentiation. Germ cell transcriptional repression occurs concurrently with inhibition of phosphorylation in the carboxy-terminal domain (CTD) of RNApolII, as well as with chromatin remodeling. The precise mechanisms involved are unknown. Here, we present evidence that a noncoding RNA transcribed by the gene polar granule component (pgc) regulates transcriptional repression in Drosophila germ cells. Germ cells lacking pgc RNA express genes important for differentiation of nearby somatic cells and show premature phosphorylation of RNApolII. We further show that germ cells lacking pgc show increased levels of K4, but not K9 histone H3 methylation, and that the chromatin remodeling Swi/Snf complex is required for a second stage in germ cell transcriptional repression. We propose that a noncoding RNA controls transcription in early germ cells by blocking the transition from preinitiation to transcriptional elongation. We further show that repression of somatic differentiation signals mediated by the Torso receptor-tyrosine kinase is important for germline development.

Animals↗
PubMed2004

Isoprenoids control germ cell migration downstream of HMGCoA reductase.

3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAr) provides attractive cues to Drosophila germ cells, guiding them toward the embryonic gonad. However, it remains unclear how HMGCoAr mediates this attraction. In a genomic analysis of the HMGCoAr pathway, we found that the fly genome lacks several enzymes required for cholesterol biosynthesis, ruling out cholesterol and cholesterol-derived proteins as mediators of PGC migration. Genetic analysis of the pathway revealed that two enzymes, farnesyl-diphosphate synthase and geranylgeranyl-diphosphate synthase, required for the production of isoprenoids, act downstream of HMGCoAr in germ cell migration. Consistent with a role in geranylgeranylation, embryos deficient in geranylgeranyl transferase type I show germ cell migration defects. Our data, together with similar findings in zebrafish, implicate an isoprenylated protein in germ cell attraction. The specificity and evolutionary conservation of the HMGCoAr pathway for germ cells suggest that an attractant common to invertebrates and vertebrates guides germ cells in early embryos.

Alkyl and Aryl Transferases↗
PubMed2004

How different is Venus from Mars? The genetics of germ-line stem cells in Drosophila females and males.

In the fruit fly Drosophila melanogaster, both spermatogenesis and oogenesis rely on germ-line stem cells (GSCs). Intensive research has revealed many of the molecules and pathways that underlie GSC maintenance and differentiation in males and females. In this review, we discuss new studies that, some differences notwithstanding, highlight the similarities in the structural and molecular strategies used by the two sexes in GSC maintenance and differentiation. These include the tight control that somatic support cells exert on every aspect of GSC function and the similar molecular mechanisms for physical attachment, cell-cell signaling and gap-junction communication. Some common principles underlying GSC biology in the fly may be applied to stem cells in other organisms.

Animals↗
PubMed2003

Tre1, a G protein-coupled receptor, directs transepithelial migration of Drosophila germ cells.

In most organisms, germ cells are formed distant from the somatic part of the gonad and thus have to migrate along and through a variety of tissues to reach the gonad. Transepithelial migration through the posterior midgut (PMG) is the first active step during Drosophila germ cell migration. Here we report the identification of a novel G protein-coupled receptor (GPCR), Tre1, that is essential for this migration step. Maternal tre1 RNA is localized to germ cells, and tre1 is required cell autonomously in germ cells. In tre1 mutant embryos, most germ cells do not exit the PMG. The few germ cells that do leave the midgut early migrate normally to the gonad, suggesting that this gene is specifically required for transepithelial migration and that mutant germ cells are still able to recognize other guidance cues. Additionally, inhibiting small Rho GTPases in germ cells affects transepithelial migration, suggesting that Tre1 signals through Rho1. We propose that Tre1 acts in a manner similar to chemokine receptors required during transepithelial migration of leukocytes, implying an evolutionarily conserved mechanism of transepithelial migration. Recently, the chemokine receptor CXCR4 was shown to direct migration in vertebrate germ cells. Thus, germ cells may more generally use GPCR signaling to navigate the embryo toward their target.

Animals↗
PubMed2003

An essential role of DmRad51/SpnA in DNA repair and meiotic checkpoint control.

Rad51 is a conserved protein essential for recombinational repair of double-stranded DNA breaks (DSBs) in somatic cells and during meiosis in germ cells. Yeast Rad51 mutants are viable but show meiosis defects. In the mouse, RAD51 deletions cause early embryonic death, suggesting that in higher eukaryotes Rad51 is required for viability. Here we report the identification of SpnA as the Drosophila Rad51 gene, whose sequence among the five known Drosophila Rad51-like genes is most closely related to the Rad51 homologs of human and yeast. DmRad51/spnA null mutants are viable but oogenesis is disrupted by the activation of a meiotic recombination checkpoint. We show that the meiotic phenotypes result from an inability to effectively repair DSBs. Our study further demonstrates that in Drosophila the Rad51-dependent homologous recombination pathway is not essential for DNA repair in the soma, unless exposed to DNA damaging agents. We therefore propose that under normal conditions a second, Rad51-independent, repair pathway prevents the lethal effects of DNA damage.

Alleles↗
PubMed2003

Identification and analysis of mutations in bob, Doa and eight new genes required for oocyte specification and development in Drosophila melanogaster.

The Drosophila oocyte develops from a cluster of 16 interconnected cells that derive from a common progenitor. One of these cells, the oocyte, arrests in meiosis. The other cells endoreplicate their DNA and produce mRNAs and proteins that they traffic to the oocyte along a polarized microtubule cytoskeleton shared by the entire cyst. Therefore, Drosophila oogenesis is an attractive system for the study of cell cycle control and cell polarity. We carried out a clonal screen on the right arm of chromosome 3 for female sterile mutations using the FLP-FRT-ovo(D) system to identify new genes required for early oogenesis. We identified alleles of oo18 RNA binding protein (orb) and Darkener of apricot (Doa), which had previously been shown to exhibit oogenesis defects. We also identified several lethal alleles of the male sterile mutant, bobble (bob). In addition, we identified eight new lethal complementation groups that exhibit early oogenesis phenotypes. We analyzed mutant clones to determine the aspects of oogenesis disrupted by each complementation group. We assayed for the production and development of egg chambers, localization of ORB to and within the oocyte, and proper execution of the nurse cell cycle (endoreplication of DNA) and the oocyte cell cycle (karyosome formation). Here we discuss the identification, mapping, and phenotypic characterization of these new genes: omelet, soft boiled, hard boiled, poached, fried, over easy, sunny side up, and benedict.

Alleles↗
PubMed2003

l(3)malignant brain tumor and three novel genes are required for Drosophila germ-cell formation.

To identify genes involved in the process of germ-cell formation in Drosophila, a maternal-effect screen using the FLP/FRT-ovoD method was performed on chromosome 3R. In addition to expected mutations in the germ-cell determinant oskar and in other genes known to be involved in the process, several novel mutations caused defects in germ-cell formation. Mutations in any of three genes [l(3)malignant brain tumor, shackleton, and out of sync] affect the synchronous mitotic divisions and nuclear migration of the early embryo. The defects in nuclear migration or mitotic synchrony result in a reduction in germ-cell formation. Mutations in another gene identified in this screen, bebra, do not cause mitotic defects, but appear to act upstream of the localization of oskar. Analysis of our mutants demonstrates that two unique and independent processes must occur to form germ cells-germ-plasm formation and nuclear division/migration.

Animals↗