Biology subjects

Jagla, T.

Publications and source records attributed to Jagla, T..

5 recordsLinked to original sources

bioRxiv2022

Deregulations of miR-1 and its target Multiplexin promote dilated cardiomyopathy associated with myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy. It is caused by the excessive expansion of non-coding CTG repeat, which when transcribed affect functions of RNA-binding factors. Specifically, MBNL1 is sequestered in nuclear foci while CELF1 is stabilised, with adverse effects on alternative splicing, processing and stability of a large set of muscular and cardiac transcripts. Among these effects, inefficient processing and down-regulation of muscle- and heart-specific miRNA, miR-1, has been reported in DM1 patients, but the impact of reduced miR-1 on DM1 pathogenesis was unknown. Here, we used Drosophila DM1 models to explore miR-1 involvement in cardiac dysfunction in DM1. We found that miR-1 down-regulation in the heart led to dilated cardiomyopathy (DCM), a DM1-associated phenotype. We then combined in silico screening for miR-1 targets with transcriptional profiling of DM1 cardiac cells to identify miR-1 target genes with potential roles in DCM. We identified Multiplexin (Mp) as a new cardiac miR-1 target involved in DM1. Mp and its human ortholog Col15A1 were both highly enriched in cardiac cells of DCM-developing DM1 flies and in heart samples from DM1 patients with DCM, respectively. Importantly, when overexpressed in the heart, Mp induced DCM, whereas its attenuation ameliorated the DCM phenotype in aged DM1 flies. Reduced levels of miR-1 and consecutive up-regulation of its target Mp/Col15A1 are thus critical in DM1-associated DCM.

genetics↗

bioRxiv2020

Automated monitoring of animal behaviour with barcodes and convolutional neural networks

Barcode-based tracking of individuals revolutionizes the study of animal behaviour, but further progress hinges on whether specific behaviours can be monitored. We achieve this goal by combining information obtained from the barcodes with image analysis through convolutional neural networks. Applying this novel approach to a challenging test case, the honeybee hive, we reveal that food exchange among bees generates two distinct social networks with qualitatively different transmission capabilities.

systems biology↗

bioRxiv2020

Individual differences in honey bee (Apis mellifera) behavior enabled by plasticity in brain gene regulatory networks

Understanding the regulatory architecture of phenotypic variation is a fundamental goal in biology, but connections between gene regulatory network (GRN) activity and individual differences in behavior are poorly understood. We characterized the molecular basis of behavioral plasticity in queenless honey bee (Apis mellifera) colonies, where individuals engage in both reproductive and non-reproductive behaviors. Using high-throughput behavioral tracking, we discovered these colonies contain a continuum of phenotypes, with some individuals specialized for either egg-laying or foraging and "generalists" that perform both. Brain gene expression and chromatin accessibility profiles were correlated with behavioral variation, with generalists intermediate in behavior and molecular profiles. Models of brain GRNs constructed for individuals revealed that transcription factor (TF) activity was highly predictive of behavior, and behavior-associated regulatory regions had more TF motifs. These results provide new insights into the important role played by brain GRN plasticity in the regulation of behavior, with implications for social evolution.

genomics↗

bioRxiv2019

New muscle identity code components identified by TRAP control shape and size of muscle subsets in Drosophila

A combinatorial code of identity transcription factors (iTFs) specifies the diversity of muscle types in Drosophila. We previously showed that two iTFs, Lms and Ap, play critical role in the identity of a subset of larval body wall muscles, the lateral transverse (LT) muscles. Intriguingly, a small portion of ap and lms mutants displays an increased number of LT muscles, a phenotype that recalls pathological split muscle fibers in human. However, genes acting downstream of Ap and Lms to prevent these aberrant muscle feature are not known. Here, we applied a cell type specific translational profiling (TRAP) to identify gene expression signatures underlying identity of muscle subsets including the LT muscles. We found that Gelsolin (Gel) and dCryAB, both encoding actin-interacting proteins, displayed LT muscle prevailing expression positively regulated by, the LT iTFs. Loss of dCryAB function resulted in LTs with irregular shape and occasional branched ends also observed in ap and lms mutant contexts. In contrast, enlarged and then split LTs with a greater number of myonuclei formed in Gel mutants while Gel gain of function resulted in unfused myoblasts, collectively indicating that Gel regulates LTs size and prevents splitting by limiting myoblast fusion. Thus, dCryAB and Gel act downstream of Lms and Ap and contribute to preventing LT muscle branching and splitting. Our findings offer first clues to still unknown mechanisms of pathological muscle splitting commonly detected in human dystrophic muscles and causing muscle weakness.

developmental biology↗

bioRxiv2018

Straightjacket/α 2δ 3 deregulation is associated with cardiac conduction defects in Myotonic Dystrophy type 1

Cardiac conduction defects decrease life expectancy in myotonic dystrophy type 1 (DM1), a complex toxic CTG repeat disorder involving misbalance between two RNA- binding factors, MBNL1 and CELF1. How this pathogenic DM1 condition translates into cardiac conduction disorders remains poorly understood. Here, we simulated MBNL1 and CELF1 misbalance in the Drosophila heart and identified associated gene deregulations using TU-tagging based transcriptional profiling of cardiac cells. We detected deregulations of several genes controlling cellular calcium levels and among them increased expression of straightjacket/2{delta}3 that encodes a regulatory subunit of a voltage-gated calcium channel. Straightjacket overexpression in the fly heart leads to asynchronous heart beating, a hallmark of affected conduction, whereas cardiac straightjacket knockdown improves these symptoms in DM1 fly models. We also show that ventricular 2{delta}3 expression is low in healthy mice and humans but significantly elevated in ventricular muscles from DM1 patients with conduction defects. Taken together, this suggests that reducing the straightjacket/2{delta}3 transcript levels in ventricular cardiomyocytes could represent a strategy to prevent conduction defects and in particular intraventricular conduction delay associated with DM1 pathology.

genomics↗