Biology subjects

Urena, E.

Publications and source records attributed to Urena, E..

3 recordsLinked to original sources

bioRxiv2024

E93 controls adult differentiation by repressing broad in Drosophila

In Drosophila melanogaster, successful development relies on the precise coordination of both spatial and temporal regulatory axes. The temporal axis governs stage-specific identity and developmental transitions through a number of genes, collectively forming the Metamorphic Gene Network. Among these, Ecdysone inducible protein 93F (E93) serves as the critical determinant for adult specification, but its mechanism of action remains unclear. Here, we found that, rather than acting as an instructive signal, E93 promotes adult differentiation through the repression of the pupal specifier broad (br). In the absence of E93, sustained high levels of Br during the pupal stage strongly represses pupal-specific enhancers that are essential for the terminal differentiation of the wing. We also show that Br represses the pupal-enhancers during the larval and prepupal stages preventing the premature implementation of the adult genetic program, and that it also dampens the activity of larval enhancers during the latter stages of larval development. This mechanism of action seems to be a derived feature acquired in Diptera, as in the coleopteran Tribolium castaneum, repression of br by E93 is not sufficient to allow adult differentiation. In summary, our study elucidates the crucial role of the intricate interplay between E93 and Br as the governing mechanism in the process of terminal differentiation in Drosophila. This discovery holds significant implications for advancing our understanding of the evolution of insect metamorphosis.

developmental biology↗

bioRxiv2022

Gba1 deletion causes immune hyperactivation and microbial dysbiosis through autophagic defects

Mutations in the GBA1 gene cause the lysosomal storage disorder Gaucher disease (GD) and are the greatest genetic risk factor for Parkinsons disease (PD). Communication between gut and brain and immune dysregulation are increasingly being implicated in neurodegenerative disorders such as PD. Here, we show that flies lacking the Gba1b gene, the main fly orthologue of GBA1, display widespread innate immune up-regulation, including gut inflammation and brain glial activation. We also demonstrate gut dysfunction in flies lacking Gba1b, with increased intestinal transit time, gut barrier permeability and microbiome dysbiosis. Remarkably, modulating the microbiome of Gba1b knockout flies, by raising them under germ-free conditions, can partially ameliorate lifespan, locomotor and some neuropathological phenotypes. Lastly, direct stimulation of autophagy by rapamycin treatment achieves similar beneficial effects. Overall, our data reveal that the gut microbiome drives systemic immune activation in Gba1b knockout flies and that reducing innate immune response activation either by eliminating the microbiota or clearance of immunogens by autophagy may represent potential therapeutic avenues for GBA1-associated neurodegenerative disease.

neuroscience↗

bioRxiv2021

Sexual identity of enterocytes regulates rapamycin-mediated intestinal homeostasis and lifespan extension

Pharmacological attenuation of mTOR by rapamycin and other compounds presents a promising route for delay of ageing-related pathologies, including intestinal cancers. Here, we show that rapamycin treatment in Drosophila extends lifespan in females but not in males. Female-specific, age-related gut pathology and impaired intestinal barrier function are both markedly slowed by rapamycin treatment, mediated by increased autophagy. Upon rapamycin treatment, female intestinal enterocytes increase autophagy, via the H3/H4 histone-Bchs axis, while male enterocytes show high basal levels of autophagy that do not increase further upon rapamycin treatment. Sexual identity of enterocytes alone, determined by the expression of transformerFemale, dictates sexually dimorphic cell size, H3/H4-Bchs expression, basal rates of autophagy, fecundity, intestinal homeostasis and extension of lifespan in response to rapamycin. This study highlights that tissue sex determines regulation of metabolic processes by mTOR and the efficacy of mTOR-targeted, anti-ageing drug treatments.

physiology↗