Background Maternal diabetes has been associated with a risk of neurodevelopmental disorders (NDDs) in offspring, though the common co-occurrence of autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD) and intellectual disability (ID) is rarely considered, nor is the potential for confounding by shared familial factors (e.g. genetics). Methods This population-based cohort study used data from Psychiatry Sweden, a linkage of Swedish national registers, to follow 2 369 680 individuals born from 1987 to 2010. We used population-averaged logit models to examine the association between exposure to maternal type 1 diabetes mellitus (T1DM), pre-gestational type 2 diabetes mellitus (T2DM) or gestational diabetes mellitus (GDM), and odds of NDDs in offspring. Subgroup analysis was then performed to investigate the timings of GDM diagnosis during pregnancy and its effect on the odds of NDDs in offspring. We compared these results to models considering paternal lifetime T1DM and T2DM as exposures. Results Overall, 45 678 individuals (1.93%) were diagnosed with ASD, 20 823 (0.88%) with ID and 102 018 (4.31%) with ADHD. All types of maternal diabetes were associated with odds of NDDs, with T2DM most strongly associated with any diagnosis of ASD (odds ratioadjusted 1.37, 95% confidence interval 1.03–1.84), ID (2.09, 1.53–2.87) and ADHD (1.43, 1.16–1.77). Considering common co-morbid groups, the associations were strongest between maternal diabetes and diagnostic combinations that included ID. Paternal T1DM and T2DM diagnoses were also associated with offspring NDDs, but these associations were weaker than those with maternal diabetes. Diagnosis of GDM between 27 and 30 weeks of gestation was generally associated with the greatest risk of NDDs in offspring, with the strongest associations for outcomes that included ID. Conclusion The association of maternal diabetes with NDDs in offspring varies depending on the co-morbid presentation of the NDDs, with the greatest odds associated with outcomes that included ID. Results of paternal-comparison studies suggest that the above associations are likely to be partly confounded by shared familial factors, such as genetic liability.
Extrinsic cues trigger the local translation of specific mRNAs in growing axons via cell surface receptors. The coupling of ribosomes to receptors has been proposed as a mechanism linking signals to local translation but it is not known how broadly this mechanism operates, nor whether it can selectively regulate mRNA translation. We report that receptor-ribosome coupling is employed by multiple guidance cue receptors and this interaction is mRNA-dependent. We find that different receptors associate with distinct sets of mRNAs and RNA-binding proteins. Cue stimulation of growing Xenopus retinal ganglion cell axons induces rapid dissociation of ribosomes from receptors and the selective translation of receptor-specific mRNAs. Further, we show that receptor-ribosome dissociation and cue-induced selective translation are inhibited by co-exposure to translation-repressive cues, suggesting a novel mode of signal integration. Our findings reveal receptor-specific interactomes and suggest a generalizable model for cue-selective control of the local proteome.
19During neuronal wiring, extrinsic cues trigger the local translation of specific mRNAs in axons 20 via cell surface receptors. The coupling of ribosomes to receptors has been proposed as a 21 mechanism linking signals to local translation but it is not known how broadly this mechanism 22 operates, nor whether it can selectively regulate mRNA translation. We report that receptor-23 ribosome coupling is employed by multiple guidance cue receptors and this interaction is 24 mRNA-dependent. We find that different receptors bind to distinct sets of mRNAs and RNA-25 binding proteins. Cue stimulation induces rapid dissociation of ribosomes from receptors and 26 the selective translation of receptor-specific mRNAs in retinal axon growth cones. Further, 27we show that receptor-ribosome dissociation and cue-induced selective translation are 28 inhibited by simultaneous exposure to translation-repressive cues, suggesting a novel mode 29 of signal integration. Our findings reveal receptor-specific interactomes and provide a general 30 model for the rapid, localized and selective control of cue-induced translation. 31 Lin and Holt, 2008). Unbiased detection of newly synthesized proteins in the axon 47 compartment has revealed further complexity showing that different guidance cues stimulate 48 the regulation of distinct signature sets of >100 axonal nascent proteins within just 5 mins, 49 many of which are not cytoskeletal-related , Yao et al., 2006, Wu et al., 50 2005. However, the mechanisms underlying the 51 localization and selectivity of translation are unclear. Several mechanisms are known to 52 control different aspects of axonal translation, including microRNA regulation (Bellon et al., 53 2017), mRNA modification (Yu et al., 2018), modulation of the phosphorylation of eukaryotic 54 initiation factors (Cagnetta et al., 2019), RNA-binding protein (RBP) phosphorylation (Sasaki 55 et al., 2010, Lepelletier et al., 2017, Huttelmaier et al., 2005) and receptor-ribosome coupling 56 (Tcherkezian et al. , 2010). The latter is a particularly direct and attractive mechanism to link 57 cue-specific signalling to differential mRNA translation. However, this mechanism has been 58 shown only for the Netrin-1 receptor, deleted in colorectal cancer (DCC), in commissural 59 axon growth cones and HEK293 cells (Tcherkezian et al., 2010) and it is unknown whether 60 receptor-ribosome coupling is a widespread mechanism used by different receptors and in 61 different cell types, and whether it regulates selective local translation. 62 63 Here, we show in retinal ganglion cell (RGC) axon growth cones that receptor-ribosome 64 coupling is used by several different axon guidance receptors (DCC, Neuropilin-1 and 65 Robo2), indicative of a common mechanism. Upon stimulation by specific cues, ribosomes 66 dissociate from their receptors within 2 minutes. Interestingly, the receptor-ribosome 67 interaction is mRNA-dependent, and immunoprecipitation (IP) reveals that distinct receptors 68 associate with specific RNA-binding proteins (RBPs) an...
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