Ho, M.-L. | Search bioRxiv

bioRxiv2019

Presynaptic dysfunction in CASK-related neurodevelopmental disorders

CASK-related disorders are a genetically defined group of neurodevelopmental syndromes. There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK mutation consequences and neuronal level effects using induced pluripotent stem cell-derived neurons from two mutation carriers; one male diagnosed with ASD and a female with MICPCH. We show a reduction of the CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of gene sets involved in presynaptic development and CASK protein interactors. Furthermore, CASK-deficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory-inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in brain. Our data shows that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders. HighlightsModelling of CASK-related disorders using iPSC-derived human neuronal cells CASK mutations cause dysregulation of its protein interactor partners Reduced CASK levels primarily affect inhibitory presynapse development In vitro GABAergic phenotype predicts in vivo neurotransmitter levels

genetics↗

bioRxiv2018

A genomic island of Streptomyces coelicolor harbors the self-contained regulon of an ECF sigma factor

Streptomycetes constitute the largest genus of actinobacteria, living predominantly in soil and decaying vegetation. The bacteria are widely known for their filamentous morphologies and their capacity to synthesize antibiotics and other biologically active molecules. More than a decade ago, we and others identified 22 genomic islands that Streptomyces coelicolor M145 possesses and other Streptomyces strains lack. One of these genomic islands, Genomic Island (GI) 6, encodes an extracytoplasmic function (ECF) sigma factor that we were characterizing in separate work. Here we report that artificial induction of the ECF sigma factor, which is encoded by SCO3450, causes the transcription of approximately one-fourth of GI 6, or ~26 mostly contiguous genes, to increase. More than half of the regulon encodes putative enzymes involved in small molecule metabolism. A putative haloacid dehalogenase is present. Genes encoding two putative anti-sigma factors flank SCO3450, the three genes residing within the regulon. Our data suggest that the ECF sigma factor and its regulon are a self-contained transcriptional unit that can be transferred by horizontal gene transfer. To our knowledge, only one other example has been identified of an ECF sigma factor and its contiguous regulon appearing to be transferrable by horizontal gene transfer [18,19]. Because the regulon appears not to be induced by the 44 growth conditions recently examined by Byung-Kwan Cho and colleagues [20], if it confers fitness to S. coelicolor, the regulon likely does so in as-yet unknown situations. Those situations might range from scavenging to detoxification to even communication within microbial communities.\n\nIMPORTANCEStreptomyces bacteria grow as hyphae that colonize soil and differentiate into spores when nutrients become scarce. In their terrestrial habitats, the bacteria encounter diverse conditions. Presumably so that the bacteria can cope with those conditions, the chromosomes of streptomycetes are highly dynamic, varying greatly in structure not only between species but also between closely related strains of a single species. The bacteria also have large numbers of extracytoplasmic function (ECF) sigma factors, which undoubtedly help the microorganisms respond to the plethora of challenges coming from the environment. This work illustrates these two threads of Streptomyces biology dovetailing: Genetic adaptability through horizontal gene transfer seems to have enabled Streptomyces coelicolor to acquire a self-contained transcriptional unit that consists of an ECF sigma factor and its regulon. The suggested facile movement of the regulon between microbial hosts indicates the value of the metabolism of small molecules possibly mediated by the regulon.

microbiology↗