Biology subjects

Iguchi, T.

Publications and source records attributed to Iguchi, T..

6 recordsLinked to original sources

bioRxiv2026

BRCA2 loss triggers a downward spiral of genomic instability via ROS-dependent metabolic collapse

BRCA2 plays a central role in maintaining genome integrity through homologous recombination and replication-fork protection, yet the compensatory networks sustaining BRCA2-deficient cells remain unclear. Here we show BRCA2 enforces a homeostatic mechanism aligning mitochondrial respiration with DNA repair capacity in both cancer and non-cancer contexts. Genome-wide CRISPR screening identified glutathione metabolism and base-excision repair as the key compensatory networks sustaining BRCA2-deficient cells by detoxifying mitochondria-derived reactive oxygen species. BRCA2 loss provokes an acute mitochondrial ROS surge, causing 8-oxoguanine accumulation and a systemic metabolic crisis marked by NAD+ and glutathione depletion. PARP inhibitor targets DNA replication vulnerabilities, increasing the cellular requirement for BRCA2. The resulting oxidative burden primes cells for TP53-dependent apoptosis in G1 during olaparib treatment, which extends cytotoxicity beyond canonical S-phase stress. These findings indicate BRCA2 prevents metabolic flux from outpacing repair capacity, providing a rationale for combining PARP inhibition with redox modulation to enhance efficacy and overcome resistance. HighlightsO_LIAcute BRCA2 loss induces ROS and mitochondrial dysfunction creating a metabolic scar C_LIO_LIOxidative lesions drive PARP hyperactivation and precipitate a cellular NAD crisis C_LIO_LIPARP inhibitors provoke TP53-dependent apoptosis in G1 beyond replication stress in S phase C_LIO_LIGlutathione deficiency exacerbates bone marrow failure under BRCA2 depletion C_LIO_LIBRCA2 tightly couples mitochondrial redox homeostasis to genomic maintenance C_LI

cell biology↗

bioRxiv2023

Comparative analysis of gonadal transcriptomes between turtle and alligator identifies common molecular cues activated during the temperature-sensitive period for sex determination

The mode of sex determination in vertebrates can be categorized as genotypic or environmental. In the case of genotypic sex determination (GSD), the sexual fate of an organism is determined by the chromosome composition with some having dominant genes, named sex-determining genes, that drive the sex phenotypes. By contrast, many reptiles exhibit environmental sex determination (ESD), whereby environmental stimuli drive sex determination, and most notably temperature. To date, temperature-dependent sex determination (TSD) has been found in most turtles, some lizards, and all crocodilians, but commonalities in the controlling processes are not well established. Recent innovative sequencing technology has enabled investigations into gonadal transcriptomic profiles during temperature-sensitive periods (TSP) in various TSD species which can help elucidate the controlling mechanisms. In this study, we conducted a time-course analysis of the gonadal transcriptome during the male-producing temperature (26L) of the Reeves turtle (Chinese three-keeled pond turtle) Mauremys reevesii. We then compared the transcriptome profiles for this turtle species during the TSP with that for the American alligator Alligator mississippiensis to identify conserved reptilian TSD-related genes. Our transcriptome-based findings provide an opportunity to retrieve the candidate molecular cues that are activated during TSP and compare these target responses between TSD and GSD turtle species, and between TSD species. Highlights- A time-course gonadal RNA-seq was conducted using Mauremys reevesii. - Sexual differentiation genes in males were activated at an earlier stage than the ones in females. - Turtle-alligator comparative analysis revealed novel candidate TSD genes.

developmental biology↗

bioRxiv2022

A model for generating differences in microtubules between axonal branches depending on the distance from terminals

In the remodeling of axonal arbor, the growth and retraction of branches are differentially regulated within a single axon. Although cell-autonomously generated differences in microtubule (MT) turnover are thought to be involved in selective branch regulation, the cellular system whereby neurons generate differences of MTs between axonal branches has not been clarified. Because MT turnover tends to be slower in longer branches compared with neighboring shorter branches, feedback regulation depending on branch length is thought to be involved. In the present study, we generated a model of MT lifetime in axonal terminal branches by adapting a length-dependent model in which parameters for MT dynamics were constant in the arbor. The model predicted that differences in MT lifetime between neighboring branches could be generated depending on the distance from terminals. In addition, the following points were predicted. Firstly, destabilization of MTs throughout the arbor decreased the differences in MT lifetime between branches. Secondly, differences of MT lifetime existed even before MTs entered the branch point. In axonal MTs in primary neurons, treatment with a low concentration of nocodazole significantly decreased the differences of detyrosination (deTyr) and tyrosination (Tyr) of tubulins, indicators of MT turnover. Expansion microscopy of the axonal shaft before the branch point revealed differences in deTyr/Tyr modification on MTs. Our model recapitulates the differences in MT turnover between branches and provides a feedback mechanism for MT regulation that depends on the axonal arbor geometry.

neuroscience↗

bioRxiv2021

Laterally biased diffusion of males of the water flea Daphnia magna

The water flea Daphnia magna is a representative example of zooplankton living in freshwater environments. They primarily propagate via asexual reproduction under normal and healthy environmental conditions. Environmental stimuli that signal a shift to disadvantageous conditions induce D. magna to change their mode of reproduction from asexual to sexual reproduction. During the sexual reproduction phase, they produce special tough eggs (resting eggs), which can survive severe environmental conditions. Despite our increased understanding of their mating behaviours, the sex-specific characteristics of swimming behaviours among daphnid species are poorly understood. In this study, we analysed the swimming patterns and dynamics of female and male adult D. magna. First, we found laterally biased diffusion of males in contrast to the homogeneous, nondirectional diffusion of females. Second, computer modelling analysis using a discrete-time Markov chain simulation, in which the frequencies of turning behaviour were evaluated as probability distributions, explained the greater diffusion of males in the horizontal direction. Under the presumption that high diffusion in the horizontal direction increases the probability of encountering a distant mate, these findings led us to hypothesise that male D. magna increase genotype heterogeneity by effectively selecting the probability distributions of certain motion parameters. Summary statementsWe analysed the swimming behaviours of adult water flea Daphnia magna, and found apparent sexual differences: laterally biased diffusion of males in contrast to the nondirectional diffusion of females.

animal behavior and cognition↗

bioRxiv2017

Repeated co-option of a conserved gene regulatory module underpins the evolution of the crustacean carapace, insect wings and other flat outgrowths

Summary statementThe genes vestigial, scalloped and wingless comprise a conserved regulatory module that was co-opted repeatedly for the evolution of flat structures, such as insect wings, and crustacean carapace, tergites and coxal plates.\n\nSummaryHow novelties arise is a key question in evolutionary developmental biology. The crustacean carapace is a novelty that evolved in the early Cambrian. In an extant crustacean, Daphnia magna, the carapace grows from the body wall as a double-layered sheet with a specialized margin. We show that the growing margin of this carapace expresses vestigial, scalloped and wingless, genes that are known to play key roles in regulating growth at the insect wing margin. RNAi-mediated knockdown of scalloped and wingless impair carapace development, indicating that carapace and wing might share a common mechanism for margin outgrowth. However, carapace and wings arise in different parts of the body and their margins have different orientations, arguing that these structures have independent evolutionary origins. We show that scalloped is also expressed at the margin of unrelated flat outgrowths (tergites and coxal plates) in the distantly related crustacean Parhyale hawaiensis. Based on these observations, we propose that the vestigial-scalloped-wingless gene module has a common role in the margin of diverse flat structures, originating before the divergence of major crustacean lineages and the emergence of insects. Repeated co-option of this module occurred independently in the carapace, wing and other flat outgrowths, underpinning the evolution of distinct novelties in different arthropod lineages.

developmental biology↗

bioRxiv2017

Developmental Downregulation of LIS1 Expression Limits Axonal Extension and Allows Axon Pruning

The robust axonal growth and regenerative capacities of young neurons decrease substantially with age. This developmental downregulation of axonal growth may facilitate axonal pruning and neural circuit formation but limits functional recovery following nerve damage. While external factors influencing axonal growth have been extensively investigated, relatively little is known about the intrinsic molecular changes underlying the age-dependent reduction in regeneration capacity. We report that developmental downregulation of LIS1 is responsible for the decreased axonal extension capacity of mature dorsal root ganglion (DRG) neurons. In contrast, exogenous LIS1 expression or endogenous LIS1 augmentation by calpain inhibition restored axonal extension capacity in mature DRG neurons and facilitated regeneration of the damaged sciatic nerve. The insulator protein CTCF suppressed LIS1 expression in mature DRG neurons, and this reduction resulted in excessive accumulation of phosphoactivated GSK-3{beta} at the axon tip, causing failure of the axonal extension. Conversely, sustained LIS1 expression inhibited developmental axon pruning in the mammillary body. Thus, LIS1 regulation may coordinate the balance between axonal growth and pruning during maturation of neuronal circuits.\n\nSummary StatementDevelopmental downregulation of LIS1 coordinates the balance between axonalelongation and pruning, which is essential for proper neuronal circuit formation but limits nerve regeneration.

neuroscience↗