Papers Selected in 2010


 Review on Cancer models in C. elegans.


 Mechanisms of trastuzumab (Herceptin) resistance.

  

Peroxidasins play crucial roles in development and reveal a new role for peroxidasins as extracellular inhibitors of axonal regeneration.

 

Review on morphogenesis: novel imaging methods, modeling, mechanical tension, and the role of junctions as signal integrators.

 

FMI-1 is a cell-type dependent axon guidance factor with different domain requirements for its different functions in pioneers and followers.

 

 

trans-generational inheritance of olfactory imprinting in C. elegans

 

P granules are not required to specify the germline in C. elegans.

 

Roles for PVD and FLP neurons:Noxious signals perceived by PVD and FLP promote an escape behavior consisting of increased speed, reduced pauses and reversals, and inhibition of egg-laying.

 

Review of trans generational epigenetic regulation in the germline.

 

Hemmingsson et al. show that C. elegans can be used to characterize cisplatin resistance mechanisms and propose that rationally designed drugs against ASNA-1 can sensitize cancer cells to cisplatin.

 

A way to visualize alternative splicing in vivo.

Using a C. elegans mutant as a drug screening toll of r spinal muscular atrophy.

 

An example of the TAT peptide crossing membranes in C. elegans.

 

kat-1 is required for the extension of lifespan and enhanced thermotolerance mediated by overexpression of the deacetylase gene sir-2.1

 

Reproductive aging in C. elegans and humans share many aspects including oocyte quality

 

Review on autophagy and longevity in C. elegans.

 

Diverse cell fate and cell polarity regulators control common mechanisms of morphogenesis in C. elegans.

 

The worm is even more like bacteria! Now you can use plasmids that carry antibiotic resistance genes to select for transgenic worms.

 

Inappropriate protein aggregation are hallmarks of neurodegenerative disorders including Parkinson's Huntington's and Alzheimer's disease.  van Ham et al. conducted a suppressor C. elegans screen for protein aggregation and identified MOAG-4 (modifier of aggregation 4) which is homologus to  SERF1A and SERF2 in humans.  See also:

 

Who would have thought your online gaming could lead to a nature paper! Link to Foldit

 

http://www.genemania.org

The evolution of trans-splicing. 

 

Theveneau et al. used xenopus neural crest cells as a models to show groups of cells (attached by  N-cadherin) are better at interpreting and responding to a chemotactic gradient (Sdf1) when compared to single cells.

 

ERK MAPK pathway increases longevity.  This longevity is consistent to what we see in vab-1 mutant worms, which have increased MAPK in oocyte maturation as well as increased DAF-18/PTEN.

 

 A review on RTK signaling [PDF]

 

Mice housed in an enriched environment (EE) showed decreased tumor growth. This is mediated through the expression of BDNF in the hypothalamus, which in turn shuts down the the fat hormone leptin.

Note EE is complex as the stress hormone levels are actually higher in EE mice. 

 

Here the authors show that the "pseudo gene" PTENP1 competes with micro RNAs that inhibit the PTEN gene. Therefore they provide a functional role for PTENP1 where it can protect the PTEN gene by sequestering away mircro RNAS that would normally target the 3'UTR of the PTEN gene. Thus PTENP1 "pseudo gene" acts as a bona fide tumour suppressor. This provocative regulation opens up the possibility of other so called "pseudo genes" have similar function.

 

Overlap extension PCR: A neat way to clone PCR products into any plasmid without using restriction enzymes or ligase. Note constructs used in this paper conform to the iGEM BioBrick standard. See Supplementary Material. Here is another method called Inverse Fusion PCR cloning. And another one called Exponential Megapriming PCR.  Also see Gibson Assembly method and follow up.

 

Is the concept of free will an illusion that has been selected for in human evolution? 

 

There is increased EGFR activity in PTEN deficient cells, and .PTEN knockdown confers resistance to EGFR kinase inhibitors. Vivanco et al. show that  PTEN  stabilizes a complex between the  Cbl E3 igase with EGFR, which targets EGFR for ubiquitinylation and degradation.

 

Phototransduction in the photoreceptor cell ASJ required a G protein–dependent cGMP pathway and the taste receptor homolog LITE-1. Phototransduction in ASJ does not required typical PDEs.

 

Modified FACS to sort worms!

 

Fleming et al. report on the phenotypic characterization of unc-34 the C. elegans  Ena/VASP ortholog. UNC-34 has roles in cell migration and genetically interacts with Wnt signaling in ALM polarity. 

 

 

More microfluidic devices for C. elegans.

 

The first report of a ser/thr phosphatase  (LET-92) regulating axon guidance.

 

Gene targeting in C. elegans!

 

A novel approach to use a temperature sensitive MEC-8 dependent RNA splicing to turn genes on or off. The mec-2

intron is specifically spliced out by MEC-8. Therefore you can insert this intron into any gene to regulate its splicing in a temperature dependent manner. The authors used this method for therde-1 gene to show you can get temperature sensitive RNAi. 

 

ten-1 encodes a transmembrane protein called Teneurin.  It is synthetic lethal with sax-3, unc-34 and unc-73.

 

Burns et al. provide structural features of drug-like small molecules that increase the likelihood of it working on C.elegans.

 

Morgan et al. used a small molecules that inhibit Ras-ERK signalling and showed that they could reprogram germ cells to switch from sperm production to oocytes.

 

 

HIF-1 prevents DNA-damaged induced germline apoptosis by inhbiting CEP-1/p53. Surprisingly, it does this in a differen tissue by transcriptionally up regulating  the tyrosinase TYR-2 in the ASJ sensory neurons. TYR-2 in turn is secreted by ASJ to antagonize CEP-1 in the germline.

 

 

Two papers from the Hobert and Moerman labs showing the feasibility of whole genome sequencing to identify EMS induced mutations.

 

Selected by Jun: Recent review that cites our work and possible connection of Eph and mTOR pathways.

 

Monoclonal antibodies for C. elegans available here.

 

Selected by Jun:  Expressing the SID-1 receptor in neurons (normally they don't) causes worms to be more sensitive to neuronal RNAi by feeding. Interestingly the SID-1 receptor acts as a sink for the dsRNA an non-neuronal tissues are reduced in their RNAi ability making this strain a useful tool to study the role of lethal genes in the nervous system.

 

Review on C. elegans sperm and oocyte signaling. With insight into understanding human diseases like ALS and cancer.

 

DCC associates with the translation initiation machinery and when the netrin ligand binds DCC it causes the the release of ribosomes and translation initiation factors to promote localized protein translation. Also see this preview.

 

Selected by Jun: A brief report that ROBO1 is cleaved and the intracellular part is found in the nucleus. What is the role of this receptor in the nucleus? That is the key question.

 

 

Matus et al. used previous genome-wide RNAi data to identify genes that gave a Protruding Vulva (Pvul) phenotype. Using these genes, they further tested which ones caused specific defects in Anchor Cell (AC) basement invasions. They identified 99 genes that promote cell invasion. They identified know genes involved in cell invasions verifying the validity of their screen. But, but most of the genes identified have not been previously been implicated in invasion or metastasis, in particular genes that encode for the cct complex (eg. cct-5) and lit-1 (a NEMO-like kinase). They went on to show the human orthologs of CCT-5 and LIT-1/NLK indeed have pro-invasion roles using a human carcinoma metastasis assay. This work is a beautiful example of how studying an in vivo process like AC invasion in C. elegans can identify human genes that regulate cell invasion and metastasis. 

 

A role for Ephrin-B2 independent of receptor binding. The PDZ binding domain is necessary for cell contraction and membrane blebbing.

 

Ghosh and Emmons use a swimming assay to quiescence in C. elegans. PKG (EGL-4) promotes quiescence as expected from previous results and here they report that the protein phosphatase calcineurin (TAX-6) promotes swimming. TAX-6 appears to function in the sensory neurons while EGL-4 appears to act downstream of acetylcholine release from motor neurons.

 

 

Some advice on lab management

 

Genetic and biochemical analysis reveal that ARR-1 functions to regulate DAF-2 signaling via direct interaction with MPZ 1 PDZ domain. ARR 1 and MPZ 1 are found in a complex with the PTEN ortholog DAF 18, and regulates DAF-2 signaling in vivo.

 

Elena Pasquale reviews Eph Receptor signalling in cancer and highlights some of the new research that makes Eph receptors promising targets for cancer therapy. Note there is mention of our Eph/PTEN interaction in C. elegans.

 

Selected by Jun: This paper gives a possible reason that accounts for "incomplete penetrance". They found "that expression in the wild-type network was highly regular, but that mutations to components of this network that are incompletely penetrant for loss of intestinal cells led to large variations in the expression of a downstream gene. These variations were subsequently thresholded to yield alternative cell fates, showing that incomplete penetrance can result from stochastic fluctuations in gene expression when mutations compromise mechanisms that normally buffer such variability.

    A novel method to image individual mRNA molecules was used:

see also Tuning In to Noise: Epigenetics and Intangible Variation

A preview on a paper describing how two small molecule inhibitors are rendered ineffective when their target kinases are involved in protein-protein interaction.  This highlights the need for in vivo kinetics of inhibition. Original paper Hoshi et al. (2010).

 

The authors express each of the 2 Robo receptors in each of the three distinct spatial and temporal patterns of the three robo genes (termed "robo swap"). It's not a Robo combinatorial protein code per se that is required for lateral positioning of axons but  but the difference in gene expression.  In contrast, structural differences are critical in midline crossing decisions, Robo 1 to prevent crossing and Robo2 to promote crossing.

 

Science news report on a recent article in BMC Evolutionary Biology suggesting that the "Asian Flush" mutation may have shaped human evolution as it might have protected farmers from the hazards of drinking alcohol. Many East Asian populations have mutations in alcohol dehydrogenase (ADH)  or aldehyde dehdrogenase (ALDH). Which can lead to high levels of acetlyaldehyde  (metabolic product of ADH on ethanol) leading to the red face, nausea headaches etc.

Zhuang et al. show that the over expression of EphA2 is an contributor to trastuzumab (aka Herceptin)) resistance. Activated EphA2 amplifies signaling through the phosphoinositide 3-kinase(PI3K)/Akt and MAPK pathways in resistant cells.

A Review on signal transduction synthetic biology some recent progress and limitations are discussed. Also, see this essay.

 

 

Sex determining genes regulate Robo signaling to influence midline crossing in Drosophila.

 

PTEN loss reduces eIF2alpha phosphoylation. The PKR kinase  is required to phosphorylate eIF2alpha and is dependent on the PTEN PDZ-binding motif. Thus PTEN can regulate protein synthesis (loss of PTEN has reduction of eIF2alpha phosphoylation) and they provide another example of PTEN function of the PI3K signaling pathway.  Note in worms the homolog of PKR ispek-1.  Also in worms loss of semaphorin/plexin signaling leads to increased eIF2alpha  phosphorylation and causes translation repression.

 

 

The Wellcome Trust Sanger Institute sequence the genomes from a malignant melanoma and a lung cancer patient. The melanoma genome contained more than 30,000 mutations (187 with non-synonymous a.a. changes)  and the lung cancer contained more than 23,000 mutations.  This implies that a typical smoker would acquire one mutation for every 15 cigarettes smoked.   There is not one gene that stands out as a "lung cancer gene" But the CHD7 was found to be mutated in several SCLC.  From the melanoma BRAF V600E and a deletion of PTEN confirm these as "driver" mutations.