Wolfram syndrome 1 regulates sleep in dopamine receptor neurons by modulating calcium homeostasis.

Sleep disruptions are quite common in psychological disorders, but the underlying mechanism remains obscure. Wolfram syndrome 1 (WS1) is an autosomal recessive disease mainly characterized by diabetes insipidus/mellitus, neurodegeneration and psychological disorders. It is caused by loss-of function mutations of the WOLFRAM SYNDROME 1 (WFS1) gene, which encodes an endoplasmic reticulum (ER)-resident transmembrane protein. Heterozygous mutation carriers do not develop WS1 but exhibit 26-fold higher risk of having psychological disorders. Since WS1 patients display sleep abnormalities, we aimed to explore the role of WFS1 in sleep regulation so as to help elucidate the cause of sleep disruptions in psychological disorders. We found in Drosophila that knocking down wfs1 in all neurons and wfs1 mutation lead to reduced sleep and dampened circadian rhythm. These phenotypes are mainly caused by lack of wfs1 in dopamine 2-like receptor (Dop2R) neurons which act to promote wake. Consistently, the influence of wfs1 on sleep is blocked or partially rescued by inhibiting or knocking down the rate-limiting enzyme of dopamine synthesis, suggesting that wfs1 modulates sleep via dopaminergic signaling. Knocking down wfs1 alters the excitability of Dop2R neurons, while genetic interactions reveal that lack of wfs1 reduces sleep via perturbation of ER-mediated calcium homeostasis. Taken together, we propose a role for wfs1 in modulating the activities of Dop2R neurons by impinging on intracellular calcium homeostasis, and this in turn influences sleep. These findings provide a potential mechanistic insight for pathogenesis of diseases associated with WFS1 mutations.

A Modified Actin (Gly65Val Substitution) Expressed in Cotton Disrupts Polymerization of Actin Filaments Leading to the Phenotype of Ligon Lintless-1 (Li1) Mutant.

Dynamic remodeling of the actin cytoskeleton plays a central role in the elongation of cotton fibers, which are the most important natural fibers in the global textile industry. Here, a high-resolution mapping approach combined with comparative sequencing and a transgenic method revealed that a G65V substitution in the cotton actin Gh_D04G0865 (GhACT17D in the wild-type) is responsible for the Gossypium hirsutum Ligon lintless-1 (Li1) mutant (GhACT17DM). In the mutant GhACT17DM from Li1 plant, Gly65 is substituted with valine on the lip of the nucleotide-binding domain of GhACT17D, which probably affects the polymerization of F-actin. Over-expression of GhACT17DM, but not GhACT17D, driven by either a CaMV35 promoter or a fiber-specific promoter in cotton produced a Li1-like phenotype. Compared with the wild-type control, actin filaments in Li1 fibers showed higher growth and shrinkage rates, decreased filament skewness and parallelness, and increased filament density. Taken together, our results indicate that the incorporation of GhACT17DM during actin polymerization disrupts the establishment and dynamics of the actin cytoskeleton, resulting in defective fiber elongation and the overall dwarf and twisted phenotype of the Li1 mutant.

Genetic fine mapping and candidate gene analysis of the Gossypium hirsutum Ligon lintless-1 (Li1) mutant on chromosome 22(D).

Ligon lintless-1 (Li1) is a Gossypium hirsutum mutant that is controlled by a dominant gene that arrests the development of cotton fiber after anthesis. Two F2 mapping populations were developed from mutant (Li1 × H7124) F1 plants in 2012 and 2013; each was composed of 142 and 1024 plants, respectively. Using these populations, Li1 was mapped to a 0.3-cM region in which nine single-strand conformation polymorphism markers co-segregated with the Li1 locus. In the published G. raimondii genome, these markers were mapped to a region of about 1.2 Mb (the Li1 region) and were separated by markers that flanked the Li1 locus in the genetic map, dividing the Li1 region into three segments. Thirty-six genes were annotated by the gene prediction software FGENESH (Softberry) in the Li1 region. Twelve genes were candidates of Li1, while the remaining 24 genes were identified as transposable elements, DNA/RNA polymerase superfamily or unknown function genes. Among the 12 candidate genes, those encoding ribosomal protein s10, actin protein, ATP synthase, and beta-tubulin 5 were the most-promising candidates of the Li1 mutant because the function of these genes is closely related to fiber development. High-throughput RNA sequencing and quantitative PCR revealed that these candidate genes had obvious differential gene expression between mutant and wild-type plants at the fiber elongation stage, strengthening the inference that they could be the most likely candidate gene of the Li1 mutant phenotype.