Biology subjects

Tan, W.-H.

Publications and source records attributed to Tan, W.-H..

6 recordsLinked to original sources

bioRxiv2024

The ER Thioredoxin-Related Transmembrane Protein TMX2 Controls Redox-Mediated Tethering of ER-Mitochondria Contacts (ERMCS)

Thioredoxin-related transmembrane proteins (TMX) of the endoplasmic reticulum (ER) have emerged as key regulators of ER membrane properties. Within the ER lumen, TMX proteins and other ER redox enzymes determine oxidative conditions, which control the formation of ER-mitochondria membrane contacts (ERMCS) and determine their function. ERMCS exhibit cytoplasmic redox nanodomains, derived from ER and mitochondrial reactive oxygen species (ROS), whose mechanistic regulation is uncharacterized. Our research has identified the ER protein TMX2, which uses its unique cytosolic thioredoxin domain to prevent cytosolic sulfenylation of mitochondrial outer membrane proteins such as TOM70 through a functional interaction with peroxiredoxin-1 (PRDX1). By doing so, TMX2 interferes with the TOM70 ERMCS tethering function and reduces mitochondrial Ca2+ flux and metabolism. Recently, TMX2 mutations have been identified to cause a neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (NEDMCMS). Using TMX2-mutated NEDMCMS patient cells, we demonstrate that compromising TMX2 through mutation reproduces mitochondrial defects. In a fly in vivo model, TMX2 knockdown manifests predominantly in glial cells. Our results therefore provide important mechanistic insight into NEDMCMS and mechanistically link TMX2-mediated control of ERMCS to brain development and function. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/589228v2_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@809587org.highwire.dtl.DTLVardef@1d8ef0corg.highwire.dtl.DTLVardef@135fdc6org.highwire.dtl.DTLVardef@1a7f7b6_HPS_FORMAT_FIGEXP M_FIG C_FIG The transmembrane thioredoxin-related TMX2 prevents TOM70 sulfenylation at ERMCS, thus maintaining normal mitochondria metabolism in wild-type cells. TMX2 knockout leads to TOM70 sulfenylation and tight ERMCS formation. This then increases ROS production, unbalances mitochondrial lipids, and relatively shifts OXPHOS electron supply to complex II.

cell biology↗

bioRxiv2023

A novel amphibian sex determination candidate gene, evolved by structural variation in the regulatory region between X and Y

Most vertebrates develop distinct females and males, where sex is determined by repeatedly-evolved environmental or genetic triggers. Undifferentiated sex chromosomes and large genomes have caused major knowledge gaps in amphibians. Only a single master sex-determining gene is known in >8650 species, the dmrt1-paralogue (dm-w) of female-heterogametic clawed frogs (Xenopus; ZW[female]/ZZ[male]). Combining chromosome-scale female and male genomes of a non- model amphibian, the European green toad, Bufo(tes) viridis, with ddRAD- and whole genome pool-sequencing revealed a candidate master locus, governing a male-heterogametic system (XX[female]/XY[male]). Targeted sequencing across multiple taxa uncovered structural X/Y-variation in the 5-regulatory region of the gene bod1l, where a Y-specific non-coding RNA, only expressed in males, suggests that this locus may initiate sex-specific differentiation. Developmental transcriptomes and RNA in-situ hybridization show timely and spatially relevant, sex-specific ncRNA-Y and bod1l-gene expression in primordial gonads with coinciding differential H3K4me- methylation in pre-granulosa/pre-Sertoli cells, pointing to a specific mechanism of amphibian sex determination.

genomics↗

bioRxiv2021

Evaluating Sleep Disturbances in Children with Rare Genetic Neurodevelopmental Syndromes

BackgroundAdequate sleep is important for proper neurodevelopment and positive health outcomes. Sleep disturbances are more prevalent in children with genetically determined neurodevelopmental syndromes compared to typically developing counterparts. We characterize sleep behavior in Rett (RTT), Angelman (AS) and Prader-Willi (PWS) syndromes in order to identify effective approaches for treating sleep problems in these populations. We compared sleep-related symptoms across individuals with these different syndromes to each other, and to typically developing controls. MethodsChildren were recruited from the Rare Diseases Clinical Research Network (RDCRN) consortium registries; unaffected siblings were enrolled as related controls. For each participant, a parent completed multiple sleep questionnaires including: Pediatric Sleep Questionnaire (Sleep-Disordered Breathing [SDB]); Childrens Sleep Habits Questionnaire; Pediatric Daytime Sleepiness Scale. ResultsSleep data were analyzed from 714 participants, ages 2-18 years. Young children with AS had more reported sleep problems than children with RTT or PWS. Older children with RTT had more reported daytime sleepiness than those with AS or PWS. Finally, all individuals with RTT had more evidence of sleep-disordered breathing when compared to individuals with PWS. Notably, typically developing siblings were also reported to have sleep problems, except for sleep-related breathing disturbances which were associated with each of the genetic syndromes. ConclusionsIndividuals with RTT, AS and PWS frequently experience sleep problems, including sleep-disordered breathing. Screening for sleep problems in individuals with these and other neurogenetic disorders should be included in clinical assessment and managements. These data may also be useful in developing treatment strategies and in clinical trials.

genetics↗

bioRxiv2019

Population genomics reveals complex patterns of immune gene evolution in monarch butterflies (Danaus plexippus)

Immune genes presumably rapidly evolve as pathogens exert strong selection pressures on host defense, but the evolution of immune genes is also constrained by trade-offs with other biological functions and shaped by the environmental context. Thus, immune genes may exhibit complex evolutionary patterns, particularly when organisms disperse to or live in variable environments. We examined the evolutionary patterns of the full set of known canonical immune genes within and among populations of monarch butterflies (Danaus plexippus), and relative to a closely related species (D. gilippus). Monarchs represent a system with a known evolutionary history, in which North American monarchs dispersed to form novel populations across the world, providing an opportunity to explore the evolution of immunity in the light of population expansion into novel environments. By analyzing a whole-genome resequencing dataset across populations, we found that immune genes as a whole do not exhibit consistent patterns of selection, differentiation, or genetic variation, but that patterns are specific to functional classes. Species comparisons between D. plexippus and D. gilippus and analyses of monarch populations both revealed consistently low levels of genetic variation in signaling genes, suggesting conservation of these genes over evolutionary time. Modulation genes showed the opposite pattern, with signatures of relaxed selection across populations. In contrast, recognition and effector genes exhibited less consistent patterns. When focusing on genes with exceptionally strong signatures of selection or differentiation, we also found population-specific patterns, consistent with the hypothesis that monarch populations do not face uniform selection pressures with respect to immune function.

evolutionary biology↗

bioRxiv2019

Transcriptomics of monarch butterflies (Danaus plexippus) reveals strong differential gene expression in response to host plant toxicity, but weak response to parasite infection

Herbivorous insects have evolved many mechanisms to overcome plant chemical defenses, including detoxification and sequestration. Herbivores may also use toxic plants to reduce parasite infection. Plant toxins could directly interfere with parasites or could enhance endogenous immunity. Alternatively, plant toxins could favor down-regulation of endogenous immunity by providing an alternative (exogenous) defense against parasitism. However, studies on genome-wide transcriptomic responses to plant defenses and the interplay between host plant toxicity and parasite infection remain rare. Monarch butterflies (Danaus plexippus) are specialist herbivores that feed on milkweeds (Asclepias spp.), which contain toxic cardenolides. Monarchs have adapted to cardenolides through multiple resistance mechanisms and can sequester cardenolides to defend against bird predators. In addition, high-cardenolide milkweeds confer medicinal effects to monarchs against a specialist protozoan parasite (Ophryocystis elektroscirrha). We used this system to study the interplay between the effects of plant toxicity and parasite infection on global gene expression. Our results demonstrate that monarch larvae differentially express several hundred genes when feeding on A. curassavica and A. incarnata, two species that are similar in nutritional content but differ substantially in cardenolide concentrations. These differentially expressed genes include genes within multiple families of canonical insect detoxification genes, suggesting that they play a role in monarch toxin resistance and sequestration. Interestingly, we found little transcriptional response to infection. However, parasite growth was reduced in monarchs reared on A. curassavica, and in these monarchs, a small number of immune genes were down-regulated, consistent with the hypothesis that medicinal plants can reduce reliance on endogenous immunity.

genomics↗

bioRxiv2018

How symbiosis and ecological context influence the variable expression of transgenerational wing induction upon fungal infection of aphids

Aphids, like most animals, mount a diverse set of defenses against pathogens. For aphids, two of the best studied defenses are symbiont-conferred protection and transgenerational wing induction. Aphids can harbor bacterial symbionts that provide protection against pathogens, parasitoids and predators, as well as against other environmental stressors. In response to signals of danger, aphids also protect not themselves but their offspring by producing more winged than unwinged offspring as a way to ensure that their progeny may be able to escape deteriorating conditions. Such transgenerational wing induction has been studied most commonly as a response to overcrowding of host plants and presence of predators, but recent evidence suggests that pea aphids (Acyrthosiphon pisum) may also begin to produce a greater proportion of winged offspring when infected with fungal pathogens. Here, we explore this phenomenon further by asking how protective symbionts, pathogen dosage and environmental conditions influence this response. Overall, while we find some evidence that protective symbionts can modulate transgenerational wing induction in response to fungal pathogens, we observe that transgenerational wing induction in response to fungal infection is highly variable. That variability cannot be explained entirely by symbiont association, by pathogen load or by environmental stress, leaving the possibility that a complex interplay of genotypic and environmental factors may together influence this trait.

evolutionary biology↗