dictyNews
Electronic Edition
Volume 38, number 10
April 6, 2012
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Abstracts
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Live imaging of nascent RNA dynamics reveals distinct types of
transcriptional pulse regulation
Tetsuya Muramoto1, Danielle Cannon1,4, Marek Gierlinski2,3, Adam
Corrigan1,4, Geoffrey J Barton2,3 and Jonathan R Chubb1,4
Divisions of Cell and Developmental Biology1
Biological Chemistry and Drug Discovery2
Wellcome Trust Centre for Gene Regulation and Expression3,
College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
4Present address: Department of Cell and Developmental Biology and
MRC Laboratory for Molecular Cell Biology, University College London,
Gower Street, London, WC1E 6BT, UK.
PNAS, in press
Transcription of genes can be discontinuous, occurring in pulses or bursts.
It is not clear how properties of transcriptional pulses vary between different
genes. We compared the pulsing of 5 housekeeping and 5 developmentally-
induced genes by direct imaging of single gene transcriptional events in
individual living Dictyostelium cells. Each gene displayed its own
transcriptional signature, differing in probability of firing and pulse duration,
frequency and intensity. In contrast to the prevailing view from both
prokaryotes and eukaryotes that transcription displays binary behaviour,
strongly expressed housekeeping genes altered the magnitude of their
transcriptional pulses during development. These non-binary 'tunable'
responses may be better suited than stochastic switch behaviour for
housekeeping functions. Analysis of RNA synthesis kinetics using
fluorescence recovery after photobleaching implied modulation of
housekeeping gene pulse strength occurs at the level of transcription
initiation, rather than elongation. In addition, disparities between single cell
and population measures of transcript production suggested differences in
RNA stability between gene classes. Analysis of stability using RNAseq
revealed no major global differences in stability between developmental and
housekeeping transcripts, although strongly induced RNAs showed unusually
rapid decay, indicating tight regulation of expression.
Submitted by Jonathan Chubb [[log in to unmask]]
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Valentina Lo Sardo, Chiara Zuccato, Germano Gaudenzi, Barbara Vitali ,
Catarina Ramos, Marzia Tartari, Michael A. Myre, James A. Walker, Anna
Pistocchi, Luciano Conti, Marta Valenza, Binia Drung, Boris Schmidt, James
Gusella, Scott Zeitlin, Franco Cotelli, Elena Cattaneo
An evolutionary recent neuroepithelial cell adhesion function of
huntingtin implicates ADAM10-Ncadherin
Nature Neuroscience, in press
The Huntington's disease gene product, huntingtin, is indispensable for
neural tube formation but its role is obscure. We studied neurulation in
htt-null embryonic stem cells and htt-morpholino zebrafish embryos, and
found a novel, evolutionarily-recent function for this ancient protein. We
show that htt is essential for homotypic interactions between
neuroepithelial cells; it permits neurulation and rosette-formation by
regulating metalloprotease ADAM10-activity and Ncadherin-cleavage. This
function is embedded in the htt N-terminus and phenocopied by treatment
ofhtt-knock-down zebrafish with an ADAM10 inhibitor. Notably, in htt-null
cells, reversion of the rosetteless phenotype occurs only with expression
of evolutionarily-recent htt heterologues from deuterostome organisms.
Conversely, all heterologues tested, including htt from Drosophila
melanogaster and Dictyostelium discoideum, exhibit anti-apoptotic
activity. Thus, anti-apoptosis may have been one of htt's ancestral
function(s) but, in deuterostomes, htt evolved to acquire a unique
regulatory activity for controlling neural adhesion via ADAM10-Ncadherin,
with implications for brain evolution and development.
Submitted by Michael Myre [[log in to unmask]]
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Michael A. Myre
Clues to Gamma-secretase, huntingtin and Hirano body normal function
using the model organism Dictyostelium discoideum
Journal of Biomedical Science, in press
Many neurodegenerative disorders, although related by their destruction of
brain function, display remarkable cellular and/or regional pathogenic
specificity likely due to a deregulated functionality of the mutant
protein. However, neurodegenerative disease genes, for example huntingtin
(HTT), the ataxins, the presenilins (PSEN1/PSEN2) are not simply localized
to neurons but are ubiquitously expressed throughout peripheral tissues;
it is therefore paramount to properly understand the earliest
precipitating events leading to neuronal pathogenesis to develop effective
long-term therapies. This means, in no unequivocal terms, it is crucial to
understand the gene's normal function. Unfortunately, many genes are
often essential for embryogenesis which precludes their study in whole
organisms. This is true for HTT, the beta-amyloid precursor protein
(APP) and presenilins, responsible for early onset Alzheimer's
disease (AD). To better understand neurological disease in humans, many
lower and higher eukaryotic models have been established. So the question
arises: how reasonable is the use of organisms to study neurological
disorders when the model of choice does not contain neurons? Here we will
review the surprising, and novel emerging use of the model organism
Dictyostelium discoideum, a species of soil-living amoeba, as a valuable
biomedical tool to study the normal function of neurodegenerative genes.
Historically, the evidence on the usefulness of simple organisms to
understand the etiology of cellular pathology cannot be denied. But using
an organism without a central nervous system to understand diseases of the
brain? We will first introduce the life cycle of Dictyostelium, the
presence of many disease genes in the genome and how it has provided
unique opportunities to identify mechanisms of disease involving actin
pathologies, mitochondrial disease, human lysosomal and trafficking
disorders and host-pathogen interactions. Secondly, I will highlight
recent studies on the function of HTT, presenilin gamma-secretase and
Hirano bodies conducted in Dictyostelium. I will then outline the
limitations and future directions in using Dictyostelium to study disease,
and finally conclude that given the evolutionary conservation of genes
between Dictyostelium and humans and the organisms' genetic
tractability, that this system provides a fertile environment for
discovering normal gene function related to neurodegeneration and will
permit translational studies in higher systems.
Submitted by Michael Myre [[log in to unmask]]
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[End dictyNews, volume 38, number 10]
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