Faculty Bibliography
Searched for:
school:SOM
Department/Unit:Cell Biology
Total Results:
14017
A novel germ cell determinant reveals parallel pathways for germ line development in Caenorhabditis elegans
Despite the central importance of germ cells for transmission of genetic material, our understanding of the molecular programs that control primordial germ cell (PGC) specification and differentiation are limited. Here, we present findings that X nondisjunction factor-1 (xnd-1), known for its role in regulating meiotic crossover formation, is an early determinant of germ cell fates in Caenorhabditis elegans. xnd-1 mutant embryos display a novel "one PGC" phenotype due to G2 cell cycle arrest of the P4 blastomere. Larvae and adults display smaller germ lines and reduced brood sized consistent with a role for XND-1 in germ cell proliferation. Maternal XND-1 proteins are found in P4 and exclusively localized to the nucleus in the PGCs, Z2 and Z3. Zygotic XND-1 turns on shortly thereafter, at the approximately 300-cell stage, making XND-1 the earliest zygotically-expressed gene in the worm PGCs. Strikingly, a subset of xnd-1 mutants lack germ cells, a phenotype shared with nos-2, a member of the conserved Nanos family of germline determinants. We generated a nos-2 null allele and show that nos-2; xnd-1 double mutants display synthetic sterility. Further removal of nos-1 leads to almost complete sterility, with the vast majority of animals without germ cells. The sterility in xnd-1 mutants is correlated with an increase in the transcriptional activation-associated histone modification and aberrant expression of somatic transgenes. Together, these data strongly suggest that xnd-1 defines a new branch for PGC development that functions redundantly with nos-2 and nos-1 to promote germline fates by maintaining transcriptional quiescence and regulating germ cell proliferation.
PMID: 26395476
ISSN: 1477-9129
CID: 1786812
E-cadherin-defective gastric cancer cells depend on Laminin to survive and invade
Epithelial-cadherin (Ecad) deregulation affects cell-cell adhesion and results in increased invasiveness of distinct human carcinomas. In gastric cancer, loss of Ecad expression is a common event and is associated with disease aggressiveness and poor prognosis. However, the molecular mechanisms underlying the invasive process associated to Ecad dysfunction are far from understood. We hypothesized that deregulation of cell-matrix interactions could play an important role during this process. Thus, we focussed on LM-332, which is a major matrix component, and in Ecad/LM-332 crosstalk in the process of Ecad-dependent invasion. To verify whether matrix deregulation was triggered by Ecad loss, we used the Drosophila model. To dissect the key molecules involved and unveil their functional significance, we used gastric cancer cell lines. The relevance of this relationship was then confirmed in human primary tumours. In vivo, Ecad knockdown induced apoptosis; nonetheless, at the invasive front, cells ectopically expressed Laminin A and betaPS integrin. In vitro, we demonstrated that, in two different gastric cancer cell models, Ecad-defective cells overexpressed Laminin gamma2 (LM-gamma2), beta1 and beta4 integrin, when compared with Ecad-competent ones. We showed that LM-gamma2 silencing impaired invasion and enhanced cell death, most likely via pSrc and pAkt reduction, and JNK activation. In human gastric carcinomas, we found a concomitant decrease in Ecad and increase in LM-gamma2. This is the fi rst evidence that ectopic Laminin expression depends on Ecad loss and allows Ecad-dysfunctional cells to survive and invade. This opens new avenues for using LM-gamma2 signalling regulators as molecular targets to impair gastric cancer progression.
PMCID:4581612
PMID: 26246502
ISSN: 1460-2083
CID: 2450482
damidseq_pipeline: an automated pipeline for processing DamID sequencing datasets
UNLABELLED:DamID is a powerful technique for identifying regions of the genome bound by a DNA-binding (or DNA-associated) protein. Currently, no method exists for automatically processing next-generation sequencing DamID (DamID-seq) data, and the use of DamID-seq datasets with normalization based on read-counts alone can lead to high background and the loss of bound signal. DamID-seq thus presents novel challenges in terms of normalization and background minimization. We describe here damidseq_pipeline, a software pipeline that performs automatic normalization and background reduction on multiple DamID-seq FASTQ datasets. AVAILABILITY AND IMPLEMENTATION/METHODS:Open-source and freely available from http://owenjm.github.io/damidseq_pipeline. The damidseq_pipeline is implemented in Perl and is compatible with any Unix-based operating system (e.g. Linux, Mac OSX). CONTACT/BACKGROUND:o.marshall@gurdon.cam.ac.uk SUPPLEMENTARY INFORMATION/BACKGROUND:Supplementary data are available at Bioinformatics online.
PMCID:4595905
PMID: 26112292
ISSN: 1367-4811
CID: 5193292
Downstream Consequences of Exercise Through the Action of BDNF
Physical exercise produces many beneficial responses in the brain, which affect cognitive function, blood flow, neurogenesis and resistance to injury. However, the exact mechanisms whereby exercise produces an induction in the brain are not well understood. A significant consequence is the induction of growth factors, such as Brain-derived Neurotrophic Factor (BDNF). Cognitive decline that occurs with aging, as well as progression of neurodegenerative diseases, are strongly correlated with decreases in BDNF. In this article, we discuss the properties of neurotrophins and the mechanisms that can account for the ability of exercise to promote brain plasticity through BDNF.
PMCID:5939187
PMID: 29765838
ISSN: 2213-6312
CID: 3121072
Rapid Bioinformatic Identification of Thermostabilizing Mutations
Ex vivo stability is a valuable protein characteristic but is laborious to improve experimentally. In addition to biopharmaceutical and industrial applications, stable protein is important for biochemical and structural studies. Taking advantage of the large number of available genomic sequences and growth temperature data, we present two bioinformatic methods to identify a limited set of amino acids or positions that likely underlie thermostability. Because these methods allow thousands of homologs to be examined in silico, they have the advantage of providing both speed and statistical power. Using these methods, we introduced, via mutation, amino acids from thermoadapted homologs into an exemplar mesophilic membrane protein, and demonstrated significantly increased thermostability while preserving protein activity.
PMCID:4601007
PMID: 26445442
ISSN: 1542-0086
CID: 1793182
Mincle Signaling Exacerbates Autoimmune Hepatitis [Meeting Abstract]
ISI:000361119700332
ISSN: 1879-1190
CID: 2802912
Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF
PMCID:4755714
PMID: 26367794
ISSN: 1476-4687
CID: 1779142
The cellular basis of hybrid dysgenesis and Stellate regulation in Drosophila
During normal tissue development, the accumulation of unrepaired cellular and genomic damage can impair growth and ultimately leads to death. To preserve cellular integrity, cells employ a number of defense mechanisms including molecular checkpoints, during which development is halted while dedicated pathways attempt repair. This process is most critical in germline tissues where cellular damage directly threatens an organism's reproductive capacity and offspring viability. In the fruit fly, Drosophila melanogaster, germline development has been extensively studied for over a century and the breadth of our knowledge has flourished in the genomics age. Intriguingly, several peculiar phenomena that trigger catastrophic germline damage described decades ago, still endure only a partial understanding of the underlying molecular causes. A deeper reexamination using new molecular and genetic tools may greatly benefit our understanding of host system biology. Among these, and the focus of this concise review, are hybrid dysgenesis and an intragenomic conflict that pits the X and Y sex chromosomes against each other.
PMCID:4674331
PMID: 26451497
ISSN: 1879-0380
CID: 1794792
Tenofovir disoproxil fumarate (TDF) reduces perinatal transmission of Hepatitis B virus in highly viremic mothers: A multi-center, prospective, randomized and controlled study [Meeting Abstract]
Background: Data on TDF use during pregnancy for preventing mother-to-child transmission (MTCT) of hepatitis B virus (HBV) are scarce. Methods: Hepatitis B E antigen (HBeAg)-positive mothers with HBV DNA levels >200,000 IU/mL were randomized 1:1 to receive either TDF from gestation week 30-32 to postpartum week 4 or no treatment, and were followed-up until postpartum week 28. All infants received immunoprophylaxis. The primary measurement was the MTCT rate, while endpoints included TDF safety, maternal HBV DNA reduction at delivery, and HBeAg or hepatitis B s antigen loss/seroconversion at postpartum week 28. Results: Among the 200 mothers enrolled in 5 regions of the country, 180 completed the study. At postpartum week 28, the MTCT rate was significantly lower in infants from TDF-treated mothers when compared to those from non-treated mothers, both on per-protocol analysis (0% vs. 6.82%, P = 0.013) and intention-to-treat analysis (5.16% vs. 18.0%, P = 0.007). The safety profile was similar between groups, with no difference in birth defect rates (2.11% with TDF exposure vs. 1.14% without exposure, P = 1.00). HBV DNA levels decreased to <200,000 IU/mL in 68% (66/97) of TDFtreated mothers before delivery compared to 2.0% (2/100) of non-treated mothers (P < 0.001). The HBV serologic outcome did not differ between groups. Conclusions: TDF therapy in late pregnancy for highly viremic mothers effectively reduced MTCT. The treatment was well tolerated, and no safety concerns were identified. TDF therapy should be strongly considered for mothers whose HBV DNA levels exceeded 200,000 IU/mL and started at gestation week 30-32. (Table Presented)
EMBASE:72078186
ISSN: 0270-9139
CID: 1874752
Progenitor Cell Dysfunctions Underlie Some Diabetic Complications
Stem cells and progenitor cells are integral to tissue homeostasis and repair. They contribute to health through their ability to self-renew and commit to specialized effector cells. Recently, defects in a variety of progenitor cell populations have been described in both preclinical and human diabetes. These deficits affect multiple aspects of stem cell biology, including quiescence, renewal, and differentiation, as well as homing, cytokine production, and neovascularization, through mechanisms that are still unclear. More important, stem cell aberrations resulting from diabetes have direct implications on tissue function and seem to persist even after return to normoglycemia. Understanding how diabetes alters stem cell signaling and homeostasis is critical for understanding the complex pathophysiology of many diabetic complications. Moreover, the success of cell-based therapies will depend on a more comprehensive understanding of these deficiencies. This review has three goals: to analyze stem cell pathways dysregulated during diabetes, to highlight the effects of hyperglycemic memory on stem cells, and to define ways of using stem cell therapy to overcome diabetic complications.
PMCID:4607762
PMID: 26079815
ISSN: 1525-2191
CID: 1632222
