Biology subjects

Leopold, P.

Publications and source records attributed to Leopold, P..

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↗

bioRxiv2025

Drosophila storage proteins promote both the rate and the duration of tumor growth

Amino acid storage proteins, such as serum albumin in mammals, are known to accumulate within tumors, but their precise contribution to tumor biology remains unclear. Using both cachectic and non-cachectic tumor models in Drosophila, we observed that fat body-derived hexamerins accumulate in the tumors through a selective uptake process. Disabling this uptake led to a marked reduction in tumor growth, demonstrating that hexamerins are used as a nutrient source to support cancer progression. Hexamerin uptake also supports expression of the relaxin-like Dilp8 by the tumor, inhibiting ecdysone production and extending the growth period. This coupling between nutrient uptake by the tumor and inhibition of the developmental progression exerts a full diversion of the host resources. Functional parallels with mammalian albumins suggest evolutionarily conserved mechanisms with potential implications for cancer biology.

cancer biology↗

bioRxiv2025

Genes required for Mycobacterium tuberculosis to survive the transition from aerosol to pulmonary alveolar lining fluid and early infection in a model of transmission

Mycobacterium tuberculosis (Mtb) must survive multiple changes in environment for aerosol transmission. Our genome-wide screen for rehydration of modeled aerosols in surrogate pulmonary alveolar lining fluid identified a survival-sustaining role for 22 genes not required for survival during earlier stages of transmission, 20 of which are non-essential in routine culture. Thirteen genes were also needed for Mtb to survive in alveolar macrophages after passing through the earlier stages of transmission. Nine 9 of the 13 were needed for full infectivity of aerosols in mice. Seven of the genes sustaining the intra-alveolar survival of aerosolized Mtb are likely to regulate Mtbs uptake, catabolism or synthesis of lipids as regulated by cAMP. Our results reveal a dynamic form of conditional essentiality that only emerges after bacteria experience a sequence of other pathophysiologically relevant conditions. These findings enlarge Mtbs candidate transmission survival genome with stage-specific genes encoding potential targets for blocking tuberculosis transmission.

microbiology↗

bioRxiv2025

A switch in the mode of tissue growth extends the growth phase of Drosophila wing primordia during early pupal development

Understanding how final organ size is established during development raises two key questions: how organs increase their mass and how they stop growing upon reaching an appropriate size. While organ growth is driven by conserved signaling pathways, the mechanisms underlying growth arrest remain elusive. Studies on Drosophila imaginal wing discs have provided a model whereby final organ size coincides with an arrest of cell proliferation at the end of the larval phase. Here, through 3D reconstruction and volume measurements, we show that wing discs grow continuously throughout the larva-to-pupa (L/P) transition and proceed to growth arrest later during the pupal period. This supplemental growth phase involves a switch at the L/P transition that uncouples proliferation from tissue growth, with an important contribution from Insulin/IGF signaling. These findings challenge the existing model of imaginal wing development and open new avenues for our understanding of growth arrest and organ size determination.

developmental biology↗

bioRxiv2023

A temporal allocation of amino acid resources ensures fitness and body allometry

Organisms have evolved strategies to store resources and overcome periods of low or no nutrient access including transient shortages or longer non-feeding developmental transitions. Holometabolous insects like Drosophila represent an attractive model to study resource allocation during development since they alternate feeding and non-feeding periods. Amino acids are essential components for tissue growth and renewal, but the strategies used for their storage remain largely unexplored. Here, we uncover a 2-step mechanism for the temporal production, storage and use of specific storage proteins called hexamerins. Moreover, we show that modulating amino acid storage affects the relative growth of organs across developmental phases and, as a consequence, alters body allometry and adult fitness.

developmental biology↗

bioRxiv2021

A local insulin reservoir ensures developmental progression in condition of nutrient shortage in Drosophila

Insulin/IGF signalling (IIS) controls many aspects of development and physiology. In Drosophila, a conserved family of insulin-like peptides (Ilp) is produced by brain neurosecretory cells and exerts systemic functions. Here, we describe the local uptake and storage of Ilps in the Corpora Cardiaca (CC), a group of alpha cell homolog that produces the glucagon-like hormone AKH. Dilp uptake relies on the expression of Impl2, an IGF-BP that accumulates in the CCs. During nutrient shortage, this specific reserve of Ilps is released and activates IIS in a paracrine manner in the prothoracic gland, securing accelerated entry into pupal development through the production of the steroid hormone ecdysone. We therefore uncover a sparing mechanism whereby local Ilp storage and release activates the production of steroids and ensures early developmental progression in adverse food conditions. Highlights- Dilps are uptaken by CC cells through the IGF-BP Imp-L2 - the CC-Dilp store is released upon nutrient shortage and activates IIS through CC projections on the PG - upon nutrient shortage, IIS activation in the PG ensures an accelerated transition from larval feeding stage to metamorphosis.

developmental biology↗

bioRxiv2020

Dilp8 controls a time window for tissue size adjustment in Drosophila

The control of organ size mainly relies on precise autonomous growth programs. However, organ development is subject to random variations, called developmental noise, best revealed by the fluctuating asymmetry observed between bilateral organs. The developmental mechanisms ensuring bilateral symmetry in organ size are mostly unknown. In Drosophila, null mutations for the relaxin-like hormone Dilp8 increase wing fluctuating asymmetry, suggesting that Dilp8 plays a role in buffering developmental noise. Here we show that size adjustment of the wing primordia involves a peak of Dilp8 expression that takes place sharply at the end of juvenile growth. Wing size adjustment relies on a crossorgan communication involving the epidermis as the source of Dilp8. We identify ecdysone signaling as both the trigger for epidermal dilp8 expression and its downstream target in the wing primordia, thereby establishing reciprocal feedback between the two hormones as a systemic mechanism controlling organ size precision. Our results reveal a hormone-based time window ensuring fine-tuning of organ size and bilateral symmetry.

developmental biology↗

bioRxiv2020

An Oatp transporter-mediated steroid sink promotes tumor-induced cachexia in Drosophila

Cancer cachexia is a multifactorial syndrome associated with many types of tumors and characterized by a combination of anorexia, loss of body weight, catabolic alterations and systemic inflammation. We developed a tumor model in Drosophila larvae causing a cachexia-like syndrome, and used it to evaluate the role of steroid hormone imbalance in cachectic alterations. Cachectic larvae show reduced levels of the circulating steroid ecdysone. Artificially importing ecdysone in the tumor using the Oatp74D importer aggravates cachexia, while feeding animals with ecdysone rescues cachectic defects. This suggests that a steroid sink induced by the tumor promotes catabolic alterations in healthy tissues. We find that Oatp33Eb, another member of this family of transporters, is specifically induced in tumors promoting cachexia. Blocking Oatp33Eb in cachectic tumors restores circulating ecdysone and reverses cachectic alterations. Oatp transporters are induced in several types of hormone-dependent tumors, suggesting that a similar sink effect could modify hormonal balance in cachectic cancer patients. Highlights- We used the Drosophila larva as a model to study hormonal imbalance in tumor-induced cachexia. - Steroid (ecdysone) levels are reduced in cachectic tumor-bearing larvae. - Steroid import by the tumor reduces circulating hormone levels and induces cachexia. - The Oatp33Eb transporter is specifically upregulated in cachectic tumors and its inhibition rescues both circulating steroid levels and metabolic/tissue homeostasis. - Specific Oatp genes are found upregulated in human tumors with high prevalence of cachexia.

developmental biology↗

bioRxiv2018

Inter-organ growth coordination is mediated by the Xrp1/Dilp8 axis in Drosophila

How organs scale with other body parts is not mechanistically understood. We have addressed this question using the Drosophila imaginal disc model. When growth of one disc domain is perturbed, other parts of the disc and other discs slow down their growth, maintaining proper inter-disc and intra-disc proportions. We show here that the relaxin-like Dilp8 is required for this inter-organ coordination. Our work also reveals that the stress-response transcription factor Xrp1 plays a key role upstream of dilp8 in linking organ growth status with non-autonomous/systemic growth response. In addition, we show that the small ribosomal subunit protein RpS12 is required to trigger Xrp1-dependent non-autonomous response. Our work demonstrates that RpS12, Xrp1 and Dilp8 constitute a new, independent regulatory module that ensures intra- and inter-organ growth coordination during development.

developmental biology↗