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Mutations in the family of neurexins (NRXN1, NRXN2and NRXN3) have been repeatedly identified in patients with autism spectrum disorder (ASD) and schizophrenia (SCZ). However, it remains unclear how these DNA variants affect neurexin functions and thereby predispose to these neurodevelopmental disorders. Understanding both the wild-type and pathologic roles of these genes in the brain could help unveil biological mechanisms underlying mental disorders. In this regard, numerous studies have focused on generating relevant loss-of-function (LOF) mammalian models. Although this has increased our knowledge about their normal functions, the potential pathologic role(s) of these human variants remains elusive. Indeed, after reviewing the literature, it seems apparent that a traditional LOF-genetic approach based on complete LOF might not be sufficient to unveil the role of these human mutations. First, these genes present a very complex transcriptome and total-LOF of all isoforms may not be the cause of toxicity in patients, particularly given evidence that causative variants act through haploinsufficiency. Moreover, human DNA variants may not all lead to LOF but potentially to intricate transcriptome changes that could also include the generation of aberrant isoforms acting as a gain-of-function (GOF). Furthermore, their transcriptomic complexity most likely renders them prone to genetic compensation when one tries to manipulate them using traditional site-directed mutagenesis approaches, and this could act differently from model to model leading to heterogeneous and conflicting phenotypes. This review compiles the relevant literature on variants identified in human studies and on the mouse models currently deployed, and offers suggestions for future research.

Venomous marine cone snails produce a unique and remarkably diverse range of venom peptides (conotoxins and conopeptides) that have proven to be invaluable as pharmacological probes and leads to new therapies. Conus catusis a hook-and-line fish hunter from clade I, with ∼20 conotoxins identified, including the analgesic ω-conotoxin CVID (AM336). The current study unravels the venom composition of C. catuswith tandem mass spectrometry and 454 sequencing data. From the venom gland transcriptome, 104 precursors were recovered from 11 superfamilies, with superfamily A (especially κA-) conotoxins dominating (77%) their venom. Proteomic analysis confirmed that κA-conotoxins dominated the predation-evoked milked venom of each of six C. catusanalyzed and revealed remarkable intraspecific variation in both the intensity and type of conotoxins. High-throughput FLIPR assays revealed that the predation-evoked venom contained a range of conotoxins targeting the nAChR, Cav, and Navion channels, consistent with α- and ω-conotoxins being used for predation by C. catus. However, the κA-conotoxins did not act at these targets but induced potent and rapid immobilization followed by bursts of activity and finally paralysis when injected intramuscularly in zebrafish. Our venomics approach revealed the complexity of the envenomation strategy used by C. catus,which contains a mix of both excitatory and inhibitory venom peptides.

Abstract: Prevention of muscle fiber degeneration is a key issue in the treatment of muscular dystrophies such as Duchenne Muscular Dystrophy (DMD). It is widely postulated that existing pharmaceutical compounds might potentially be beneficial to DMD patients, but tools to identify them are lacking. Here, by using a Caenorhabditis elegans model of dystrophin-dependent muscular dystrophy, we show that the neurohormone serotonin and some of its agonists are potent suppressors of muscle degeneration. Inhibitors of serotonin reuptake transporters, which prolong the action of endogenous serotonin, have a similar effect. Moreover, reduction of serotonin levels leads to degeneration of non-dystrophic muscles. Our results demonstrate that serotonin is critical to C. elegans striated muscles. These findings reveal a new fonction of serotonin in striated muscles.