Developmental regulation of progenitor aging shapes long-term intestinal homeostasis in Drosophila.

Shikha Malik; Atharva Anand Mahajan; Saraswathi J Pillai; Isha Shinde; Muhamad Shameem; Sumit Pande; Pratik Chandrani; Mandar M Inamdar; Rohan J Khadilkar

doi:10.1002/1873-3468.70462

PubMed · 42723471

Developmental regulation of progenitor aging shapes long-term intestinal homeostasis in Drosophila.

Shikha Malik·Atharva Anand Mahajan·Saraswathi J Pillai·Isha Shinde·Muhamad Shameem·Sumit Pande·Pratik Chandrani·Mandar M Inamdar·Rohan J Khadilkar

View original source ↗Export metadata ↓

Abstract

Aging causes disruption of tissue homeostasis, with stem cell exhaustion as a major hallmark. However, whether aging trajectories are established during development remains unexplored. Here, we demonstrate that genetic modulation of aging-associated pathways in larval adult midgut progenitors (AMPs) determines the trajectory of Drosophila adult intestinal homeostasis. Induction of aging-associated pathways in the AMPs results in aberrant proliferation, skewed differentiation, barrier dysfunction, and genomic instability. Ultimately, AMP islet architecture is destabilized and age-related molecular signatures are altered. In contrast, reversing aging-associated effects results in a decrease in the enteroendocrine population and the barrier is unaffected. Together, our findings demonstrate that aging-associated pathways are tightly regulated during early development and perturbation can hamper adult gut homeostasis, establishing AMPs as key developmental determinants.

Explore related subjects

Drosophila intestinal homeostasis progenitor aging signaling adult midgut progenitors Journal Article

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Shikha Malik, Atharva Anand Mahajan, Saraswathi J Pillai, Isha Shinde, Muhamad Shameem, Sumit Pande, Pratik Chandrani, Mandar M Inamdar, Rohan J Khadilkar. 2026-09-11. Developmental regulation of progenitor aging shapes long-term intestinal homeostasis in Drosophila.. https://doi.org/10.1002/1873-3468.70462

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2026

A Landscape of Drosophila melanogaster Disease Models: From Genetic Platforms to Cross-Disease Mechanisms and Translational Research.

Modeling human diseases using the fruit fly (Drosophila melanogaster) has established itself as a cornerstone of functional genomics and preclinical medicine. Despite its anatomical simplicity, the Drosophila genome shares remarkable functional conservation with human disease-related genes, enabling the study of complex physiological traits through accessible tissue models. Furthermore, beyond individual disease models, we propose a framework demonstrating how these diseases converge at common molecular centers, such as the breakdown of protein homeostasis, mitochondrial dysfunction, chronic inflammation, and organ-to-organ communication. Finally, we discuss strategies for integrating the Drosophila platform into drug development pipelines and establishing standards to enhance inter-laboratory reproducibility. Overall, this review highlights the enduring value of fruit flies as a model system, particularly when combined with AI-omics approaches to transform complex biological datasets into actionable therapeutic strategies.

Drosophila↗

PubMed2023

The genetic basis of adaptation to copper pollution in Drosophila melanogaster.

Introduction: Heavy metal pollutants can have long lasting negative impacts on ecosystem health and can shape the evolution of species. The persistent and ubiquitous nature of heavy metal pollution provides an opportunity to characterize the genetic mechanisms that contribute to metal resistance in natural populations. Methods: We examined variation in resistance to copper, a common heavy metal contaminant, using wild collections of the model organism Drosophila melanogaster. Flies were collected from multiple sites that varied in copper contamination risk. We characterized phenotypic variation in copper resistance within and among populations using bulked segregant analysis to identify regions of the genome that contribute to copper resistance. Results and Discussion: Copper resistance varied among wild populations with a clear correspondence between resistance level and historical exposure to copper. We identified 288 SNPs distributed across the genome associated with copper resistance. Many SNPs had population-specific effects, but some had consistent effects on copper resistance in all populations. Significant SNPs map to several novel candidate genes involved in refolding disrupted proteins, energy production, and mitochondrial function. We also identified one SNP with consistent effects on copper resistance in all populations near CG11825, a gene involved in copper homeostasis and copper resistance. We compared the genetic signatures of copper resistance in the wild-derived populations to genetic control of copper resistance in the Drosophila Synthetic Population Resource (DSPR) and the Drosophila Genetic Reference Panel (DGRP), two copper-naïve laboratory populations. In addition to CG11825, which was identified as a candidate gene in the wild-derived populations and previously in the DSPR, there was modest overlap of copper-associated SNPs between the wild-derived populations and laboratory populations. Thirty-one SNPs associated with copper resistance in wild-derived populations fell within regions of the genome that were associated with copper resistance in the DSPR in a prior study. Collectively, our results demonstrate that the genetic control of copper resistance is highly polygenic, and that several loci can be clearly linked to genes involved in heavy metal toxicity response. The mixture of parallel and population-specific SNPs points to a complex interplay between genetic background and the selection regime that modifies the effects of genetic variation on copper resistance.

Drosophila↗