Papers Selected in 2008


A novel feedback loop that promotes EphB2 activation and cell repulsion that is blocked by transcriptional targets of FGFR.

LAR tyrosine phosphatase dephosphorylates  EphB2 and this can be blocked by FGFR activation.

Review on Eph/Ephrin signaling in synaptic function

SOD gene knock outs suggests that superoxide radical (O2-) is not a major determinant of aging in C. elegans.

The authors have identified a role for the invasive form of Mena  (Mena INV) in metastasis.

In unstimulated cells, actin filaments are capped. EGF stimulation leads to PLCγ-mediated release and activation of cofilin from PIP2. Cofilin severs capped actin filaments and MenaINV binds newly generated free barbed ends. Actin filament elongation and the resulting membrane protrusion are supported by the recruitment of polymerization-competent monomers through profilin binding and the anticapping activity of Mena. Subsequently, the Arp2/3 nucleates new filaments that branch off the growing filaments.

 

See also how to shape cells and influence polarized protein trafficking.[Link]

 

Identified mutations in three timing genes (lin-4, lin-14, and lin-28) that result in either premature or delayed axon growth. These genes function independently from known directional signals as well as axon position.

The authors show that axon guidance is not only through growth cone steering, but also by the generation and stabilization of branches in the leading process. Therefore the angle at which they branch determines the possible directions to be followed.

aak-2 (AMPK) mutants enter dauer but they rapidly consume lipids stores in the hypodermis and thus have shortened lifespan. AAK-2 phosphorylates ATGL-1 to block ATGL-1 mediated triglyceride hydrolysis to ensure long-term dauer survival.  The aak-2 signaling is also required to enhance osmoregulation in the excretory system during nutrient depletion.  Narbonne and Roy's work provides a mechanism to show show the relationship between akk-2's role in lipid metabolism and life span.   Listen to Dr. Richard Roy on CBC's Quirks and Quarks

 

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A long awaited method called Mos1-mediated single-copy insertion or MosSCI  will enable C. elegans researchers to get single copy insertions at a specified site. A must read for all C. elegans biologists!

A thought provoking review on stochastic gene expression and the important consequences for cellular function.

The authors used a Y2H screen to isolate blue light-dependent interactions and identified a Cryptochome (CRY2) interacting protein, CIB1. The "bridge" in this Y2H case is blue light. They propose this blue-light dependent interaction with cryptochromes is an early photoreceptor signaling required for plant cell elongation and flowering.

 CIB1 co-receptor complex between FGFR and the G-protein -coupled A2AR. The complex is needed for modulating synaptic plasticity by synergistic increase in MEK1/2.

Here is a review on receptor-receptor interactions.

Ephrin A reverse signaling is thought to be mediated by a co-receptor complex in lipid rafts known as caveolae. Dennis O'leary's lab has shown that one of these co-receptors is the p75 neurotrophin receptor (NTR) and this complex may signal through the activation of the Src family kinase Fyn . In C. elegans trk-1 encodes the RTK most closely related to the vertebrate neurotrophin receptors.

see also this perspective   "An All-Purpose tool for Axon Guidance"

 

Deletion of PTEN promotes axon regeneration

A link between germline stem cells (GSCs) and fat metabolism and logevity.

 Loss of ephrin B2 or its receptor EphB4 leads to enlarged aortae and underdeveloped cardinal veins.

 

Richard Wilson et al. Sequenced 623 candidate cancer genes and identified 26 genes that are mutated at high frequency in several lung cancers. Including multiple Eph Receptors, and notably EphA3 it the most significantly mutated gene in the Eph family. VAB-1/Eph RTK is most similar to EphA3 intracellular region. One observed mutation in EPHA3, K761N, is located in the kinase domain at a highly conserved position analogous to FGFR2(K641) which is thought to act as a molecular brake in the kinase.

Overview of copy number, gene expression and DNA methylation in glioblastomas. Notably p53.

  

Ronald A. DePinho et al show that nervous system specific p53 and pten deletions  in the mouse CSN causes glioma phenoytpe similar to human glioblastomas.

 

Need a Halloween costume? How about a bizarre Jurassic maniraptoran?

 

 

The authors map half of the 330 PDZ domains in the human and C. elegans proteomes.

 

Selected by Sarah:  The smg-1 gene works (positively) in parallel with daf-2/age-1 signaling to regulate lifespan. Note that it is smg-1  increased longevity mutants are daf-18/pten dependent.

 

Target of Rapamycin (TOR) works in the prothoracic gland to couple nutritional input with ecdysone production and developmental timing.

Selected by Jun: he Seydoux lab show that  3′ UTRS are sufficient to specify most expression patterns in the germline-- the one exception is expression in sperm. Four RNA binding proteins, FBF-1, FBF-2, GLD-1, and MEX-3 mediate 3′ UTR-dependent repression in germline progenitors.

Review article on netrins, slits and wnts in dorsal/ventral anterior/posterior axon guidance. 

Selected by Ahmed: Axon guidance cue UNC-6/netrin and its receptor UNC-5 act throughout development to exclude synaptic vesicle and active zone proteins from the dendrite.  

A new nuclear localization signal that is kinase/phosphorylation dependent.

Metastasis is usually viewed as a late stage of cancer. That is, the tumor forms first and then a cell from the primary tumnor invades and spreads to distant location.  But an emerging view is a early dissemination model of spreading, such that a premalignant cells can move first then setup a primary tumor. See perspective by Christopher Klein.   The bottom line is that unregulated invasion and spreading is bad, therefore studying cell movements and the genes that regulate cell movement is important in understanding cancer.

Annual Review of Pathology: Mechanisms of Disease PTEN PI3K review

Science's view

Nature's view

Three studies published this week (Sept. 4th 2008) on genome sequencing of various cancers.

1. and others...

The isocitrate dehydorgenase 1 (IDH1) is mutated in 12% of Glioblatoma multiforme (GBM) patients. In C. elegans IDH1 ortholog is called F59B8.2  and is 75% identical and 85% similar over the entire protein.

2. and others...

There are 12 core signaling pathways that are affected in pancreatic cancers. The core pathways included those in which a single, frequently altered gene predominated, such as in KRAS signaling and in the regulation of the G1/S cell cycle transition; pathways in which a few altered genes predominated, such as in TGF-β signaling; and pathways in which many different genes were altered, such as in integrin signaling, regulation of invasion, homophilic cell adhesion, and small GTPase-dependent signaling.
3.   [Link to Nature Article]

Interim report from the TCGA. They analyzed more than 200 glioblastoma samples for alterations such as changes in copy number, DNA methylation and probed about half the samples for mutations in 600 genes already implicated in cancer.

Filippakopoulos et al use crystal structure analysis to show how the SH2 domain and kinase domain of the human  Fes tyrosine kinase interact to enhance catalytic activity and substrate specify. The SH2 domain binding stabilizes the Fes kinase.  This SH2-kinase interaction may be general as it also seems to stimulate Abl tyrosine kinase.

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The Warburg effect of aerobic glycolysis is a key metabolic hallmark of cancer, however  Hsu and Sabatini suggest that we need to explore beyond a glucose and energy-centric driven model of cancer metabolism to a broader one that encompasses all of the metabolic needs of a cancer cell.

 

LITE-1 a novel UV and blue light receptor in C. elegans.

 

In C. elegans there are at least 3 actin regulating pathways (WASP-WAVE, UNC-115/abLIM, and UNC-34/Ena) that act in parallel to control lamellipodia and filopodia formation during axon guidance.

 

Review on Nectin and Afadin

 

p53 inhibits mTOR signaling.

 

Oral administration AICAR (an AMPK agonist) can increase running endurance (44%) without exercise.

 

Domain based interactome of 800 proteins required for C. elegans early embryogenesis.

 

Greer et al. show that DAF-7 , a TGFb ligand, acts as a sensor to regulate fat metabolism and feeding behavior. Furthermore the perception of adverse environmental conditions can promote fat accumulation without an increase in feeding rate. They show that glutamate signaling is involved to promote fat accumulation.

 

Selected by Jun: Here Sarin et al. show that it is feasible to identify a point mutation using Illumina deep sequencing technology.  Forward genetic screens will be fashionable again as whole genome sequencing becomes more widely used." The application of whole-genome sequencing offers many unique advantages. The sequence run only takes a few days and costs are in the few-thousand dollar range, which compare favorably to the personnel and reagent costs of a traditional multi-year gene cloning project. "

 

A review on PTEN regulation

 

GLP-1 is required in neurons to maintain dauer stage while LIN-12 is needed to promote dauer recovery.

 

Autophagy is required to degrade maternal products in the oocyte and essential for preimplantation.

 

DSCAM expressing cells are attracted to netrin-1 ligand independent of DCC.

 

 

A model for how cell contacts polarize embryos radially. The PAC-1 is recruited to the inner surfaces by cell contacts and inactivates CDC-42, while CDC-42 and PAR-6 remains active on the outer surfaces.

 

Hypoxia affects axon guidance through HIF-1 up regulation of VAB-1/Eph RTK. daf-2  mutants can suppress this phenotype.

 

Automated microfluidic system for worm screening.

 

A new ligand for Eph Receptors.The VAP MSP domains are secreted ligands for Eph Receptors (presumably on adjacent or nearby cells). Mutations in VAP affect pathways involving ER and unfolded response leading to accumulation of mutant and wild-type protein (cell autonomous) as well as the failure to secrete the MSP domain (cell non autonomous). Note the C. elegans VAP-1 also binds to the VAB-1 Eph Receptor during many VAB-1 related processes.  Also see this follow up paper.

 

Recent insights to the role of autophagy in animal development.

 

 

Primary tumors can "feed" cells that have undergone metastasis. Human breast carcinomas release signals (eg. osteopontin) to stimulate the growth of otherwise indolent tumor cells located at a different site.

 

 

Glutamate release from the AWC olfactory neuron is sufficient to excite AIB (expresses GLR-1)  and inhibit AIY (expresses GLC-3) interneurons to coordinate behavioral responses.

Review on Ena/VASP function in neurites

 

and...

 

N-Cadherin , a major synaptic adhesion molecule signals to the actin cytoskeleton via AF-6 and Kalirin-7  to control dendritic spine morphology.

 

EphA4 phosphorylates Nck2 and Dok1 among the 74 identified different proteins with 248 potential Eph phosphorylation sites.

Table S2 EphA4-mediated phosphorylation of known tyrosine kinase substrates

Table S3 Putative EphA4 phosphorylation sites in Eph associated proteins

 

The PDZ protein Canoe (aka in mammals AF-6/Afadin) localizes apically to neuroblast (NB) and interacts with Partner of Inscutebale (Pins) to generate correct neuronal lineages by the  process of asymmetric NB divisions.

 

Review on Eph signaling during cell invasion.

 

Latest review on PTEN function and regulation and how manipulation of PTEN function could be used for cancer therapy.

 

 

Sensory signaling can shape the neuronal structure.

 

A method to grow cells and C. elegans in microfluid compartments.

 

Alternative splicing of Robo3 generates two isoforms with distinct expression patterns and behaviors in commissural axons.

 

MSP/sperm regulates endocytic trafficking of the VAB-1 MSP/Eph receptor contributes to the control of oocyte meiotic maturation.

see also: 

 

Cultivation of C. elegans in hypoxia reorganizes neuronal circuits to change its behavior for oxygen preference.

 

It seems like common sense what constitutes image manipulation, but here are examples caught by editors based on actual cases of digital manipulation.

 

In cancer cells the a kinase-independent EGFR can prevent autophagic cell death by maintaining intracellular glucose level through interaction and stabilization of the sodium/glucose cotransporter 1 (SGLT1).

 

MNP-1 is expressed in migrating muscle and works with INA-1 in the epidermis and VAB-1 and VAB-2/EFN-1 in the neuroblasts to promote proper muscle cell migrations in the embryo.

 

Multiple RNA binding proteins regulate nos-2 translation

 

LIN-23 (F-box protein) dependent and independent regulation of CDC-25.1 protein turnover for cell divisions in the embryo.

 

Ubiquitin-mediated degradation of CDC-25.1 is a rate-determining step for the E (gut) and P3 (muscle and germline) lineages but not others, even though CDC-25.1 and its apparent decay have been detected in all lineages. See above paper too.

 

Polo-like kinase PLK-1 and the cyclin-dependent kinase phosphatase CDC-25.1, are asymmetrically distributed in early embryos. Both proteins are required for normal cell cycles, these asymmetries are controlled by PAR proteins and the MEX-5/MEX-6, and the latter is linked to protein degradation.

 

Getting closer to a knocking  out in every gene in C. elegans

 

Andrew Chisholm's perspective on this paper:

Provides a significant role for the translation of mRNAs for cytoskeletal regulators, linking environmental cues to cytoskeletal rearrangement during cellular morphogenesis.

 

 

bus-8 encodes a glycosyltransferase, is essential for embryonic enclosure and acts in or with ephrin signaling to mediate neuroblast organisation and epidermal morphogenesis.

 

Antipshychotic drugs have a PLM phenotype like vab-1 mutants!

 

  [PDF] April 15th 2008 Science Signaling review on Ephs

 

The latest review on Ephrins and Eph Receptors

 

 RPM-1 negatively regulates axon outgrowth (PLMs) as loss of function rpm-1 mutants have PLM over expression. sax-3/robo and unc-5 mutants can suppress this overextension phenotype.glo-4 (Rab GEF) but not fsn-1 mutants have similar phenotype to rpm-1 mutants and suggest that RPM-1 regulates  axon outgrowth by controlling the trafficking of UNC-5 and SAX-3 receptors to the cell membrane. Note overexpression of SAX-3 in the touch neurons (mec-7 promoter) is sufficient to cause a PLM overextension phenotype. Overexpression of RPM-1 in the touch neurons has the opposite effect - early termination (phenocopy sax-3 and unc-5 loss of function).

The biomolecular fluorescence complementation (BiFC) assay. A protocol for use in C. elegans.

A review on the progress in the genetic analysis of neural circuits

 

Some nice work on the AIY interneuron on how it synapse onto the RIA neuron

 

Site specific recombinase works in worms!-- an approach to use it to turn on genes permanently

 

C. elegans is capable of actively responding to food levels to regulate adult ploidy. Cilated sensory neurons

sense the food and requires the cGMP-dependent kinase EGL-4 and the SMA/MAB signaling pathway.

 

SCF (skr-1, cul-1 and rbx-1) negative regulate cep-1/p53 germ cell apoptosis in response to ENU.

 

Like daf-18/PTEN ,mdf-1 mutants show L1 starved germline proliferation. mdf-1 encodes a conserved spindle assembly checkpoint (SAC) component. Proposed to work downstream of DAF-18 and AKT and it has roles independent of other SAC components (ie mdf-2--which also shows inappropriate germ cell proliferation). Interestingly mdf-1/+ (het) has a stronger prolifeation effect than the mdf-1/mdf-1 homozygotes

 

 

Somatic expression of the CXCR7 receptor sequesters SDF-1a, causing the formation of an active chemoattractant gradient that is necessary for the correct migration of zebrafish primordial germ cells.

 

To study the evolution of malignancy one must also look at the ecology of the tumor environment. This review looks at the cellular constituents of the tumor microenvironment, actively migrating from sites both local and distant that contribute to enhanced tumor cell motility, invasiveness, and survival. 

 

A role for Diaphanous formin in morphogenesis

 

AVM axon regeneration requires MIG-10/Lamellipodin (independent of UNC-40) and actin regulators UNC-34/Ena and CED-10/Rac

 

Review on Eph/ephrin signaling including recent work in C. elegans.

 

Science report on  Reddy et al 2008 on the importance of PTEN in follicle maturation. Note that PTEN was deleted specifically from the oocyte but affected follicle activation so does this mean pten deletion in the oocyte had a cell non autonomous affect on the follicle cells?

 

Use of networks to predict the effects of perturbing individual genes on the organism's phenotype.

 

 

PCR derived transgenes can give better expression than vector based ones.

 

Another recombineering approach for reporter fusions

 

Editor's comment on :

J. M. Swiercz, T. Worzfeld, S. Offermanns, ErbB-2 and Met reciprocally regulate cellular signaling via plexin-B1. J. Biol. Chem. 283, 1893-1901 (2008). [Abstract] [Full Text]

 

FAK has a nuclear role in cell survival through p53 degradation under conditions of cellular stress.

Also see:

 

 

muscle contraction without neurotransmitter or neurons. See preview by Kim and Zhen

 

 

Start those forward genetic screens! We are on the verge when whole-genome sequencing will become standard practice in labs.

 

Genes regulated by DAF-16/FOXO involved in nuclear pore complex and germline tumors.

 

Fasting does have its benefits. Dietary restriction can lead to autophagy (pronounced: Awe-Toph- agy or auto-phagy?) which has beneficial effects, but too much autophagy is not good either.

See this News and Views too:

Autophagy and the Cancer connection

Selected by Ahmed: EGL-4 a cGMP-dependent protein kinase (PKG) functions in senory neurons to regulate sleep-like behaviour in C. elegans.