Biology subjects

Estella, C.

Publications and source records attributed to Estella, C..

9 recordsLinked to original sources

bioRxiv2026

Xrp1 integrates cellular stress through different control modes in Drosophila

Cells and tissues have the ability to respond to different stresses and maintain their homeostasis. The b-Zip transcription factor Xrp1 was found to play a pivotal role in this context in Drosophila. Xrp1 is required for the response to irradiation, in genetic conditions of ribosomal protein (Rp) deficiency leading to cell competition, and more generally in mediating the Integrated Stress Response (ISR). However, how these diverse stresses converge to and activate Xrp1 is still unclear. Our results demonstrate the existence of three separate mechanisms of Xrp1 induction. In response to Rp stress, a short isoform of Xrp1 is produced and requires the function of the ribosomal protein RpS12. In response to irradiation, a specific mRNA isoform is transcriptionally induced, which encodes the Xrp1-short protein isoform, in a p53-dependent manner. In response to the ISR, the long isoform of Xrp1 is translated by the derepression of a uORF present on the Xrp1 5'UTR, a mechanism that requires eIF2 phosphorylation, RpS12, and a transcriptional induction by ATF4. Therefore, our work provides a comprehensive understanding of the role of Xrp1 in different situations of cellular stress, illustrating the complex level of integration of the mechanisms controlling this central gene.

developmental biology↗

bioRxiv2026

A signaling network motif couples protein expression levels and intracellular localization

Most of the accepted major signaling pathways incorporate a mechanism of physical separation of active versus inactive effector proteins, in the form of dynamic nucleocytoplasmic shuttling. Here, we show that when this translocation takes place as dimers, it operates as a network motif that introduces a nonlinear coupling between expression levels of a protein and its intracellular localization. This mechanism modulates the activity of the TGF-{beta} signaling cascade by affecting the location of its main effectors, the R-Smads, as well as in all signaling cascades analyzed that incorporate a dimerization step linked to nucleocytoplasmic shuttling, operating as a singular type of nonlinear network motif that does not require a loop of regulation and takes advantage of physical intracellular compartmentalization.

systems biology↗

bioRxiv2026

Genetic control of mitotic-to-meiotic transition regulates germline cell survival

AO_SCPLOWBSTRACTC_SCPLOWThe coordination between DNA damage repair and cell cycle progression is essential to ensure cell survival and organ homeostasis. This is particularly critical during gametogenesis, where germline cells first proliferate and then transition from mitosis to meiosis. Meiotic cells frequently undergo recombination, which itself implies the generation of severe DNA damage in the form of double-strand DNA breaks (DSBs) that ought to be repaired to preserve genome integrity. Here, we identify Drosophila bru1 as an essential factor in the mitotic-to-meiotic transition in the female germline. The RNA-binding protein Bru1 is a translational repressor of multiple targets, including cyclins, and is sharply upregulated at the mitotic-to-meiotic boundary. We show that loss of bru1 disrupts germline development by altering cell cycle regulation, increasing DNA damage and cellular stress, and triggering apoptosis. bru1 mutants display clear signs of accelerated mitotic activity leading to extra divisions in the germline, in agreement with their elevated Cyclin A and B levels. Importantly, slowing cell cycle progression in bru1 mutants via string/cdc25 knockdown decreases DNA damage and cell death. Mechanistically, bru1 regulates mei-W68 transcription, the topoisomerase responsible for DSB production in the germline. Higher Mei-W68 levels induce premature and ectopic DSBs, which persist longer in the mutant germline, indicating defective repair and potentially resulting in p53-mediated apoptosis. Our work classifies bru1 as a safeguard of genome integrity and germline survival during the early stages of Drosophila female gametogenesis. bru1 regulates Mei-W68 levels and DSB formation, and controls the mitotic-to-meiotic transition by influencing cell cycle progression. The existence of bru1 homologues in mammals with established roles in gametogenesis suggests a broader biological relevance of our discoveries.

developmental biology↗

bioRxiv2023

Cell proliferation and Notch signaling coordinate the formation of epithelial folds in the Drosophila leg

The formation of complex three-dimensional organs during development requires the precise coordination between patterning networks and mechanical forces. In particular, tissue folding is a crucial process that relies on a combination of local and tissue-wide mechanical forces. Here, we investigate the contribution of cell proliferation to epithelial morphogenesis using the Drosophila leg tarsal folds as a model. We reveal that tissue-wide compression forces generated by cell proliferation, in coordination with Notch signaling pathway, are essential for the formation of epithelial folds in precise locations along the proximo-distal axis of the leg. As cell numbers increase, compressive stresses arise, promoting the buckling of the epithelium and reinforcing the apical constriction of invaginating cells. Additionally, the Notch target dysfusion (dysf) plays a key function specifying the location of the folds, through the apical accumulation of F-actin and the apico-basal shortening of invaginating cells. These findings provide new insights into the intricate mechanisms involved in epithelial morphogenesis, highlighting the critical role of tissue-wide forces in shaping a three-dimensional organ in a reproducible manner.

developmental biology↗

bioRxiv2023

Temporal Dynamics of Apoptosis-Induced Proliferation in Pupal Wing Development: Implications for Regenerative Ability

The ability of animals to regenerate damaged tissue is a complex process that involves various cellular mechanisms. As animals age, they lose their regenerative abilities, making it essential to understand the underlying mechanisms that limit regenerative ability during aging. Drosophila melanogaster wing imaginal discs are epithelial structures that can regenerate after tissue injury. While significant research has focused on investigating regenerative responses during larval stages, particularly regarding the regulation and function of the JNK pathway, our comprehension of the regenerative potential of pupal wings and the underlying mechanisms contributing to the decline of regenerative responses remains limited. This study explores the temporal dynamics during pupal development of the proliferative response triggered by the induction of cell death, a typical regenerative response. Our results indicate that the apoptosis-induced proliferation response can be initiated as late as 30 hours after pupa formation (APF), when in normal circumstances cell proliferation ceases at around 20 hours APF. Furthermore, our data revealed that after 35 hours APF, cell death alone fails to induce further proliferation. Interestingly, the failure of reinitiating the cell cycle beyond this time point is not attributed to an incapacity to activate the JNK pathway. Instead, one of the constraining factors in the apoptotic-induced proliferation process during pupal development seems to be the activity level of ecdysone-responsive genes. Author SummaryAnimals have the remarkable ability to regenerate damaged tissues, but this regenerative potential diminishes with age. Understanding the mechanisms underlying age-related decline in regenerative abilities is crucial. Drosophila melanogaster wing imaginal discs provide a valuable model for studying tissue regeneration. While significant research has focused on regenerative responses during larval stages, our understanding of the regenerative potential and mechanisms in pupal wings remains limited. In this study, we investigate the temporal dynamics of the proliferative response triggered by cell death during late during the development, in pupal development. Our findings reveal that the apoptosis-induced proliferation response can occur during pupal development, even after normal cell proliferation has ceased. However, at late stages of pupal development this response does not occur. We have found that, the inability to reinitiate the cell cycle beyond this time point is influenced by the activity of the hormone ecdysone and its-responsive genes. These findings shed light on the dynamic processes involved in tissue regeneration during pupal development. This study expands our understanding of the complex interplay between cell death, proliferation, and gene activity during tissue regeneration, providing valuable insights for future research in regenerative biology.

developmental biology↗

bioRxiv2023

LACK OF APOPTOSIS CAUSES CELLULAR SENESCENCE AND TUMORIGENESIS IN DROSOPHILA EPITHELIAL CELLS

Programmed cell death (apoptosis) is a homeostasis program of animal tissues designed to remove cells that are unwanted or are damaged by physiological insults. To assess the functional role of apoptosis we have studied the consequences of subjecting Drosophila epithelial cells defective in apoptosis to stress or genetic perturbations that normally cause massive cell death. We find that many of those cells acquire persistent activity of the JNK pathway, which drives them into senescent status, characterized by arrest of cell division, cell hypertrophy, Senescent Associated {beta}-gal activity (SA-{beta}-gal), ROS production, Senescent Associated Secretory Phenotype (SASP) and migratory behaviour. We have identified two classes of senescent cells in the wing disc: 1) those that localize to the appendage part of the disc, express the upd, wg and dpp signalling genes and generate tumour overgrowths, and 2) those located in the thoracic region do not express wg and dpp nor they induce tumour overgrowths. Whether to become tumorigenic or non-tumorigenic depends on the original identity of the cell prior to the transformation. We also find that the p53 gene contributes to senescence by enhancing the activity of JNK.

developmental biology↗

bioRxiv2021

p53 pro-apoptotic activity is regulated by the G2/M promoting factor Cdk1 in response to DNA damage

Exposure to genotoxic stress promotes cell-cycle arrest and DNA repair or apoptosis. These "life" or "death" cell fate decisions often rely on the activity of the tumor suppressor gene p53. Therefore, how p53 activity is precisely regulated is essential to maintain tissue homeostasis and to prevent cancer development. Here we demonstrate that Drosophila p53 pro-apoptotic activity is regulated by the G2/M kinase Cdk1. We find that cell cycle arrested or endocycle-induced cells are refractory to ionizing radiation induced apoptosis. We show that the p53 protein is not able to bind to and to activate the expression of the pro-apoptotic genes in experimentally arrested cells. Our results indicate that p53 genetically and physically interacts with Cdk1 and that p53 pro-apoptotic role is regulated by the cell cycle status of the cell. We propose a model in which cell cycle progression and p53 pro-apoptotic activity are molecularly connected to coordinate the appropriate response after DNA damage.

developmental biology↗

bioRxiv2020

In vivo analysis of the evolutionary conserved BTD-box domain of Sp1 and Btd during Droso phila development

The Sp family of transcription factors plays important functions during development and disease. An evolutionary conserved role for some Sp family members is the control of limb development. The family is characterized by the presence of three C2H2-type zinc fingers and an adjacent 10 aa region with an unknown function called the Buttonhead (BTD) box. The presence of this BTD-box in all Sp family members identified from arthropods to vertebrates, suggests that it plays an important role during development. However, despite its conservation, the in vivo function of the BTD-box has never been studied. In this work, we have generated specific BTD-box deletion alleles for the Drosophila Sp family members Sp1 and buttonhead (btd) using gene editing tools and analyzed its role during development. Unexpectedly, btd and Sp1 mutant alleles that lack the BTD-box are viable and have almost normal appendages. However, in a sensitized background the requirement of this domain to fully regulate some of Sp1 and Btd target genes is revealed. Furthermore, we have also identified a novel Sp1 role promoting leg vs antenna identity through the repression of spineless (ss) expression in the leg, a function that also depends on the Sp1 BTD-box.

developmental biology↗

bioRxiv2020

Dpp and Hedgehog promote the Glial response to neuronal damage in the developing Drosophila Visual system

Damage in the nervous system induces a stereotypical response that is mediated by glial cells. Here, we use the eye disc to explore the mechanisms involved in promoting glial cell response after neural injuries. We demonstrate that eye glia cells rapidly respond to neuronal injury by increasing in number and undergoing morphological changes, which grant them phagocytic abilities. We found that this glial response is controlled by the activity of the long-range signalling pathways, decapentaplegic (dpp) and hedgehog (hh). These pathways are activated in the damaged region and their functions are necessary for inducing glial cell proliferation and migration to the eye discs. The latter of these two processes depends on the function of the JNK pathway, which is cooperatively activated by dpp and hh signalling.

neuroscience↗