Biology subjects

Plagnol, V.

Publications and source records attributed to Plagnol, V..

3 recordsLinked to original sources

bioRxiv2020

A gradient of Wnt activity positions the neurosensory domains of the inner ear

The auditory and vestibular organs of the inner ear and the neurons that innervate them originate from Sox2-positive and Notch-active neurosensory domains specified at early stages of otic development. Sox2 is initially present throughout the otic placode and otocyst, then it becomes progressively restricted to a ventro-medial domain. Using gain and loss-of-function approaches in the chicken otocyst, we show that these early changes in Sox2 expression are regulated in a dose-dependent manner by Wnt/beta-catenin signalling. Both high and very low levels of Wnt activity repress Sox2 and neurosensory competence. However, intermediate levels allow the maintenance of Sox2 expression and sensory organ formation. We propose that a dorso-ventral (high-to-low) gradient and wave of Wnt activity initiated at the dorsal rim of the otic placode progressively restricts Sox2 and Notch activity to the ventral half of the otocyst, thereby positioning the neurosensory competent domains in the inner ear.

developmental biology↗

bioRxiv2019

FUS ALS-causative mutations impact FUS autoregulation and the processing of RNA-binding proteins through intron retention

Mutations in the RNA-binding protein FUS cause amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease in which the loss of motor neurons induces progressive weakness and death from respiratory failure, typically only 3-5 years after onset. FUS plays a role in numerous aspects of RNA metabolism, including mRNA splicing. However, the impact of ALS-causative mutations on splicing has not been fully characterised, as most disease models have been based on FUS overexpression, which in itself alters its RNA processing functions. To overcome this, we and others have recently created knock-in models, and have generated high depth RNA-sequencing data on FUS mutants in parallel to FUS knockout. We combined three independent datasets with a joint modelling approach, allowing us to compare the mutation-induced changes to genuine loss of function. We find that FUS ALS-mutations induce a widespread loss of function on expression and splicing, with a preferential effect on RNA binding proteins. Mutant FUS induces intron retention changes through RNA binding, and we identify an intron retention event in FUS itself that is associated with its autoregulation. Altered FUS regulation has been linked to disease, and intriguingly, we find FUS autoregulation to be altered not only by FUS mutations, but also in other genetic forms of ALS, including those caused by TDP-43, VCP and SOD1 mutations, supporting the concept that multiple ALS genes interact in a regulatory network.

neuroscience↗

bioRxiv2016

Phenopolis: an open platform for harmonization and analysis of sequencing and phenotype data

SummaryPhenopolis is an open-source web server which provides an intuitive interface to genetic and phenotypic databases. It integrates analysis tools which include variant filtering and gene prioritisation based on phenotype. The Phenopolis platform will accelerate clinical diagnosis, gene discovery and encourage wider adoption of the Human Phenotype Ontology in the study of rare disease.\n\nAvailability and ImplementationA demo of the website is available at http://phenopolis.github.io (username: demo, password: demo123). If you wish to install a local copy, souce code and installation instruction are available at https://github.com/pontikos/phenopolis. The software is implemented using Python, MongoDB, HTML/Javascript and various bash shell scripts.\n\nContactn.pontikos@ucl.ac.uk\n\nSupplementary informationhttp://phenopolis.github.io

bioinformatics↗