No abstract

Prenatal maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders. How gestational timing of MIA-exposure differentially impacts downstream development remains unclear. Here, we characterize neurodevelopmental trajectories of mice exposed to MIA induced by poly I:C either early (gestational day [GD]9) or late (GD17) in gestation using longitudinal structural magnetic resonance imaging from weaning to adulthood. Early MIA-exposure associated with accelerated brain volume increases in adolescence/early-adulthood that normalized in later adulthood, in regions including the striatum, hippocampus, and cingulate cortex. Similarly, alterations in anxiety, stereotypic, and sensorimotor gating behaviours observed in adolescence normalized in adulthood. In contrast, MIA-exposure in late gestation had less impact on anatomical and behavioural profiles. Using a multivariate technique to relate imaging and behavioural variables for the time of greatest alteration, i.e. adolescence/early adulthood, we demonstrate that variation in anxiety, social, and sensorimotor gating associates significantly with volume of regions including the dorsal and ventral hippocampus, and anterior cingulate cortex. Using RNA sequencing to explore the molecular underpinnings of region-specific alterations in early MIA-exposed mice in adolescence, we observed the most transcriptional changes in the dorsal hippocampus, with regulated genes enriched for fibroblast growth factor regulation, autistic behaviours, inflammatory pathways, and microRNA regulation. This indicates that MIA in early gestation perturbs brain development mechanisms implicated in neurodevelopmental disorders. Our findings demonstrate the inherent strength of an integrated hypothesis- and data-driven approach in linking brain-behavioural alterations to the transcriptome to understand how MIA confers risk for major mental illness.

No abstract

Translation of mRNAs into proteins by the ribosome is the most important step of protein biosynthesis. Accordingly, translation is tightly controlled and heavily regulated to maintain cellular homeostasis. Ribosome profiling (Ribo‐seq) has revolutionized the study of translation by revealing many of its underlying mechanisms. However, equally many aspects of translation remain mysterious, in part also due to persisting challenges in the interpretation of data obtained from Ribo‐seq experiments. Here, we show that some of the variability observed in Ribo‐seq data has biological origins and reflects programmed heterogeneity of translation. Through a comparative analysis of Ribo‐seq data from Saccharomyces cerevisiae, we systematically identify short 3‐codon sequences that are differentially translated (DT) across mRNAs, that is, identical sequences that are translated sometimes fast and sometimes slowly beyond what can be attributed to variability between experiments. Remarkably, the thus identified DT sequences link to mechanisms known to regulate translation elongation and are enriched in genes important for protein and organelle biosynthesis. Our results thus highlight examples of translational heterogeneity that are encoded in the genomic sequences and tuned to optimizing cellular homeostasis. More generally, our work highlights the power of Ribo‐seq to understand the complexities of translation regulation.

Translation of messenger RNAs into proteins by the ribosome is the most important step of protein biosynthesis. Accordingly, translation is tightly controlled and heavily regulated to maintain cellular homeostasis. Ribosome profiling (Ribo-seq) has revolutionized the study of translation by revealing many of its underlying mechanisms. However, equally many aspects of translation remain mysterious, in part also due to persisting challenges in the interpretation of data obtained from Ribo-seq experiments. Here, we show that some of the variability observed in Ribo-seq data has biological origins and reflects programmed heterogeneity of translation. To systematically identify sequences that are differentially translated (DT) across mRNAs beyond what can be attributed to experimental variability, we performed a comparative analysis of Ribo-seq data from Saccharomyces cerevisiae and derived a consensus ribosome density profile that reflects consistent signals in individual experiments. Remarkably, the thus identified DT sequences link to mechanisms known to regulate translation elongation and are enriched in genes important for protein and organelle biosynthesis. Our results thus highlight examples of translational heterogeneity that are encoded in the genomic sequences and tuned to optimizing cellular homeostasis. More generally, our work highlights the power of Ribo-seq to understand the complexities of translation regulation.