Biology subjects

Serluca, F.

Publications and source records attributed to Serluca, F..

4 recordsLinked to original sources

bioRxiv2021

Integrative proteogenomics for differential expression and splicing variation in a DM1 mouse model

Dysregulated mRNA splicing is involved in the pathogenesis of many diseases including cancer, neurodegenerative diseases, and muscular dystrophies such as myotonic dystrophy type 1 (DM1). Comprehensive assessment of dysregulated splicing on the transcriptome and proteome level has been methodologically challenging, and thus investigations have often been targeting only few genes. Here, we performed a large-scale coordinated transcriptomic and proteomic analysis to characterize a DM1 mouse model (HSALR) in comparison to wild-type. Our integrative proteogenomics approach comprised gene- and splicing-level assessments for mRNAs and proteins. It recapitulated many known instances of aberrant mRNA splicing in DM1 and identified new ones. It enabled the design and targeting of splicing-specific peptides and confirmed the translation of known instances of aberrantly spliced disease-related genes (e.g. Atp2a1, Bin1, Ryr1), complemented by novel findings (e.g. Ywhae, Flnc, Svil). Comparative analysis of large-scale mRNA and protein expression data showed quantitative agreement of differentially expressed genes and splicing patterns between disease and wild-type. We hence propose this work as a suitable blueprint for a robust and scalable integrative proteogenomic strategy geared towards advancing our understanding of splicing-based disorders. With such a strategy, splicing-based biomarker candidates emerge as an attractive and accessible option, as they can be efficiently asserted on the mRNA and protein level in coordinated fashion. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/443842v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@593246org.highwire.dtl.DTLVardef@1f3b5bforg.highwire.dtl.DTLVardef@12113b3org.highwire.dtl.DTLVardef@947d8f_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2019

Predictive neural processing in adult zebrafish depends on shank3b

Intelligent behavior requires a comparison between the predicted and the actual consequences of behavioral actions. According to the theory of predictive processing, this comparison relies on a neuronal error signal that reflects the mismatch between an internal prediction and sensory input. Inappropriate error signals may generate pathological experiences in neuropsychiatric conditions. To examine the processing of sensorimotor prediction errors across different telencephalic brain areas we optically measured neuronal activity in head-fixed, adult zebrafish in a virtual reality. Brief perturbations of visuomotor feedback triggered distinct changes in swimming behavior and different neuronal responses. Neuronal activity reflecting sensorimotor mismatch, rather than sensory input or motor output alone, was prominent throughout multiple forebrain areas. This activity preceded and predicted the transition in motor behavior. Error signals were altered in specific forebrain regions by a mutation in the autism-related gene shank3b. Predictive processing is therefore a widespread phenomenon that may contribute to disease phenotypes.

neuroscience↗

bioRxiv2018

Genetic Architecture of Collective Behaviors in Zebrafish

Collective behaviors of groups of animals, such as schooling and shoaling of fish, are central to species survival, but genes that regulate these activities are not known. Here we parsed collective behavior of groups of adult zebrafish using computer vision and unsupervised machine learning into a set of highly reproducible, unitary, several hundred millisecond states and transitions, which together can account for the entirety of relative positions and postures of groups of fish. Using CRISPR-Cas9 we then targeted for knockout 35 genes associated with autism and schizophrenia. We found mutations in three genes had distinctive effects on the amount of time spent in the specific states or transitions between states. Mutation in immp2l (inner mitochondrial membrane peptidase 2-like gene) enhances states of cohesion, so increases shoaling; mutation in in the Nav1.1 sodium channel, scn1lab+/- causes the fish to remain scattered without evident social interaction; and mutation in the adrenergic receptor, adra1aa-/-, keeps fish close together and retards transitions between states, leaving fish motionless for long periods. Motor and visual functions seemed relatively well-preserved. This work shows that the behaviors of fish engaged in collective activities are built from a set of stereotypical states. Single gene mutations can alter propensities to collective actions by changing the proportion of time spent in these states or the tendency to transition between states. This provides an approach to begin dissection of the molecular pathways used to generate and guide collective actions of groups of animals.

animal behavior and cognition↗

bioRxiv2017

ALKALs are in vivo ligands for ALK family Receptor Tyrosine Kinases in the neural crest and derived cells.

Mutations in Anaplastic Lymphoma Kinase (ALK) are implicated in somatic and familial neuroblastoma, a paediatric tumour of neural crest-derived tissues. Recently, biochemical analyses have identified secreted small ALKAL proteins (FAM150, AUG) as potential ligands for human ALK and the related Leukocyte Tyrosine Kinase (LTK). In the zebrafish Danio rerio, DrLtk, which is similar to human ALK in sequence and domain structure, controls the development of iridophores, neural crest-derived pigment cells. Hence, the zebrafish system allows studying Alk/Ltk and Alkals involvement in neural crest regulation in vivo. Using zebrafish pigment pattern formation, Drosophila eye patterning, and cell culture-based assays, we show that zebrafish Alkals potently activate zebrafish Ltk and human ALK driving downstream signalling events. Overexpression of the three Dr Alkals cause ectopic iridophore development whereas loss of function alleles lead to spatially distinct patterns of iridophore loss in zebrafish larvae and adults. alkal loss of function triple mutants completely lack iridophores and are larval lethal as is the case for ltk null mutants. Our results provide the first in vivo evidence of (i) activation of ALK/LTK family receptors by ALKALs and (ii) an involvement of these ligand-receptor complexes in neural crest development.

developmental biology↗