The NTR/prodrug revolution: Tools for controlling cell loss and regeneration

Regeneration studies rely on experimental injuries, and the nature of the injury profoundly shapes the ensuing repair response. In zebrafish, the major injury paradigms can be broadly grouped into the following categories:

1) Physical injury: Direct tissue damage via surgical intervention that has been used successfully to study adult regeneration, including fin amputation (Pfefferli and Jaźwińska, 2015), ventricular resection (Poss et al., 2002), brain lesioning (Kroehne et al., 2011), scale removal (Cox et al., 2018; Bergen et al., 2022), and transection of both tendons (Tsai et al., 2023) and ligaments (Anderson et al., 2023). Severing of the spinal cord predictably leads to paralysis in zebrafish, but as testament to their regenerative capacity, full mobility is returned by 8 weeks (Becker et al., 1997; Reimer et al., 2008; Goldshmit et al., 2012).

Several non-surgical physical methods can be used to induce tissue damage in animal models, with their suitability largely determined by the subject’s size and developmental stage. In adult models, approaches include cryoinjury to simulate myocardial infarction (González-Rosa and Mercader, 2012; Bise et al., 2020), intense light exposure to trigger photoreceptor degeneration in retinal regeneration studies (Vihtelic and Hyde, 2000), and acoustic trauma to model inner-ear damage and hearing loss recovery (Schuck and Smith, 2009; Liang et al., 2012). The acoustic method has also been applied to larval zebrafish to target lateral line hair cells (Uribe et al., 2018). Larval and embryonic zebrafish, owing to their small size and optical transparency, permit highly precise laser ablation of single neurons (Liu and Fetcho, 1999; Muto and Kawakami, 2018; Roeser and Baier, 2003) or even individual cardiomyocytes (Matrone et al., 2013). Additionally, thermal injury has been employed in larvae to model burns and skin regeneration, revealing rapid inflammatory cell recruitment (Miskolci et al., 2019) and keratinocyte migration, but impaired sensory axon regeneration compared to mechanical injury (Fister et al., 2024).

Regardless of the method, each of these physical injury approaches perturbs tissue integrity in characteristic ways, disrupting multiple components of tissue architecture, including extracellular matrix, mesenchymal organization, and local vasculature. This disruption drives rapid physiological and robust inflammatory responses involving neutrophils and macrophages, all of which critically influence regenerative outcomes (Miskolci et al., 2019; Fister et al., 2024; Gelashvili et al., 2026).

2) Cell-specific toxins: While physical injury has provided key insights into regenerative biology, these approaches are often constrained by limited precision and cell-type specificity. Pharmacological methods offer a complementary strategy, using small molecules to induce targeted, dose-controlled damage. Table 1 summarizes representative compounds used for cell-specific ablation in zebrafish. However, many of these agents introduce off-target effects, ranging from dose-dependent systemic toxicity to unintended tissue injury, which can make downstream regenerative responses harder to interpret. For example, MPTP and MPP⁺ mainly target dopaminergic (DA) neurons but can also impact noradrenergic and serotonergic systems via uptake through their neurotransmitter transporters (Dovonou et al., 2023; Meredith and Rademacher, 2011). Similarly, aminoglycoside antibiotics, while commonly used to ablate lateral line hair cells, can also damage support cells and afferent neurons at higher concentrations, and exhibit compound-specific differences in ototoxicity (Coffin et al., 2013; Thomas and Raible, 2019; Uribe et al., 2013; Wiedenhoft et al., 2017). Streptozotocin, widely used to ablate pancreatic β-cells, is known to cause broader cytotoxicity beyond the target population (Moss et al., 2009). To achieve higher precision and reduce off-target effects, as well as expand the kinds of cells that can be ablated, the field has increasingly turned to genetic strategies. These methods allow damage to be targeted with exquisite specificity to predefined cell types (Table 1).

3) Optogenetic cell ablation: Due to the transparent nature of young zebrafish, this model is highly amenable to optogenetic techniques that enable precise, non-invasive control of cellular signaling, neuronal circuit activity, and targeted cell ablation (see reviews Varady and Distel, 2020; Baillie et al., 2021). KillerRed is a genetically encoded photosensitizer that produces reactive oxygen species (ROS) upon green or yellow light illumination, killing nearby cells (Buckley et al., 2017; Bulina et al., 2006). When expressed under cell-specific promoters, this technique allows researchers to eliminate defined cell populations in living embryos or larvae with precise spatiotemporal control (Buckley et al., 2017; Bulina et al., 2006; Teh et al., 2010). A key advantage of this method is its speed, as KillerRed-expressing cells can be ablated within hours of light exposure. This approach is particularly useful for modeling diseases in which ROS-mediated cell death is central, such as neurodegeneration (Formella et al., 2018) and cardiomyopathies (Teh and Korzh, 2014), but it has not yet been applied in conventional regeneration studies. Although speculative, this method appears best suited for discrete, optically accessible cells (Buckley et al., 2017), and is likely to be impractical for ablation of large populations, whole tissues, or cells deep within the adult body, where localized illumination is more difficult. Because this method relies on controlled optical delivery via microscopy, it also limits throughput, making high-volume studies challenging.

4) Chemogenetic, cell-specific ablation: Chemogenetic ablation relies on transgene-driven, cell-specific expression of an exogenous protein that converts an otherwise innocuous chemical into a cytotoxic agent. By eliminating only the intended population and leaving neighboring tissues intact, these methods generate narrowly focused injuries whose regenerative responses differ substantially from those induced by broader, multi-tissue physical damage. Four such chemogenetic systems established in zebrafish include:

1. Human diphtheria toxin receptor and diphtheria toxin: The human pathogen Corynebacterium diphtheriae produces diphtheria toxin (DT), which enters cells by binding the human diphtheria toxin receptor (hDTR) (Collier, 2001; Naglich et al., 1992). Because endogenous receptors in non-primates do not bind DT efficiently, these animals are naturally resistant to the toxin. This strategy allows researchers to engineer specific cell types to express hDTR, making them uniquely susceptible to DT-induced ablation (Saito et al., 2001). In mouse research, the DTR/DT system has become one of the most commonly employed strategies for conditional cell ablation, owing to its rapid and reliable elimination of targeted cell populations across many tissues. However, the method has caveats, like the fact that DT alone can cause kidney damage (Goldwich et al., 2012) and that repeated DT exposure induces production of neutralizing antibodies, preventing long-term or chronic ablation.

   • Although DTR/DT approaches are widely used in mouse studies, their application in zebrafish has been more limited (Jimenez et al., 2021; Schmitner et al., 2017). A noteworthy example is the transgenic line generated by Jimenez et al., in which hDTR driven by the hair-cell-specific myo6b promoter enabled selective depletion of sensory hair cells following DT administration, with full regeneration occurring within days (Jimenez et al., 2021). Some studies in zebrafish have instead expressed diphtheria toxin subunit A (DTA) directly in target cells (Kurita et al., 2003; Li et al., 2009), although constitutive DTA expression lacks temporal control and is not suitable for regeneration studies. Temporal control can be introduced through Cre/lox-inducible DTA systems (Sun et al., 2021), but issues such as recombination efficiency, mosaicism, and promoter leakiness may limit precision (Erhardt et al., 2025).

2. Inducible caspase systems: Caspase cascade in apoptosis begins with upstream initiator caspases (e.g. caspase 8) activated by dimerization, which then activates effector caspases (e.g. caspase 3) to execute cellular dismantling (Salvesen and Dixit, 1997; Boatright and Salvesen, 2003; Riedl and Salvesen, 2007). In zebrafish, researchers have exploited induction of caspase-8 dimerization to achieve temporal and spatial control of cell-specific ablation in two main ways: (1) activation by the FK1012 chemical inducer of dimerization (Schmitner et al., 2017; Banaszynski et al., 2006) and (2) expression of a fusion between caspase and the modified estrogen receptor ligand-binding domain (ERT2), whose activity is induced by binding of tamoxifen (Pose-Méndez et al., 2023; Weber et al., 2016; Chu et al., 2008). Compared to FK1012, tamoxifen pharmacokinetics are better characterized in zebrafish, and a convincing study showing lifelong regeneration of cerebellar Purkinje cells in zebrafish strongly supports the use of the ER-T2/tamoxifen-inducible ablation approach for probing cell loss and recovery (Pose-Méndez et al., 2023).

3. HSV-TK: The herpes simplex virus thymidine kinase (HSV-tk) has been applied in zebrafish for conditional cell ablation. Transgenic expression of this ‘suicide gene’ (here defined as a gene encoding an enzyme that converts a nontoxic prodrug into a cytotoxin; Spooner et al., 2001) in a defined cell population converts the antiviral prodrug ganciclovir into toxic nucleotides that are lethal to proliferating cells, but this dependence on cell division has limited the utility of the approach (Moro et al., 2009).

4. Nitroreductase (NTR): Bacterial nitroreductase genes (nfsB) are another class of suicide genes. These genes encode NTR, enzymes that convert nitro-containing prodrugs (e.g. nitroimidazoles and nitrofurans) into cytotoxic metabolites. As a result, transgenic animal cells expressing NTR become vulnerable to treatment with prodrugs such as metronidazole (MTZ), ronidazole (RNZ), nifurpirinol (NFP), and CB1954. Unlike HSV-TK, the NTR/MTZ system operates as a ‘cell-cycle-independent’ method for targeted cell ablation, and improved variants of NTR can efficiently ablate fully differentiated cell types (Sharrock et al., 2022; Mulligan and Mumm, 2024).

The NTR/prodrug system is now a staple of zebrafish research, although, somewhat surprisingly, the approach was first developed in the mouse. Since then, it has been adapted for use in a wide range of model organisms, including:

• Drosophila melanogaster – Teeters et al. used NTR and RNZ to ablate multiple, diverse cell types during development, demonstrating rapid, temperature-independent ablation using a simple drug-feeding protocol (Teeters et al., 2025).

• Nematostella – Gavgani et al. used NTR and NFP to ablate neurons and reveal their requirement in body-axis regeneration (Mazloumi Gavgani et al., 2025).

• Xenopus laevis – Two NTR/MTZ models, one targeting oligodendrocytes and the other rod photoreceptors, achieved reliable, cell-specific ablation with subsequent regeneration. One targeting study noted temperature-dependent NTR activity, with reduced efficiency below 22°C (Kaya et al., 2012; Langhe et al., 2017; Mannioui et al., 2018; Martinez-De Luna and Zuber, 2018).

• Medaka – Willems et al. used NTR and MTZ to conditionally ablate osteoblasts and assess regeneration following drug withdrawal (Willems et al., 2012).

• Rat – Kwak et al. applied NTR and CB1954 to ablate neonatal cerebellar and ventricular progenitors, resulting in ataxia and reduced cerebellar volume (Kwak et al., 2007).

• Zebrafish – The most extensively used model for NTR/prodrug-mediated cell ablation, with applications across a wide range of tissues to study regeneration and to model human disease (Figure 1 and Supplementary file 1).

• Mouse – The first in vivo NTR/CB1954 transgenic models were generated in mouse, where NTR expression enabled selective ablation of T cells and mammary luminal epithelial cells (Clark et al., 1997; Drabek et al., 1997). These initial studies were followed by ablation studies of adipocytes, neurons, and kidney podocytes, showing the versatility across diverse tissues of this ablation method (Felmer et al., 2002; Isles et al., 2001; Macary et al., 2010). However, most of these efforts were carried out in the context of evaluating NTR as a suicide-gene strategy for cancer therapy in humans, rather than a tool for studying cell regeneration. Subsequent work in mammals shifted toward the DTR system, which is the predominant method of chemogenetic, cell-specific ablation in mouse.

Figure 1

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The NTR/MTZ system for cell-specific ablation was first described in two 2007 studies. Pisharath et al. placed the E. coli nfsB gene (NTR) under the zebrafish insulin promoter to express an NTR-mCherry fusion in pancreatic β-cells; treatment with 10 mM MTZ produced complete β-cell loss without affecting neighboring α-cells or exocrine tissue (Pisharath et al., 2007). Curado et al. used cell-specific promoters to express CFP-NTR in cardiomyocytes, hepatocytes, and β-cells, likewise demonstrating that MTZ induced highly targeted cell death with no detectable bystander effects (Curado et al., 2007). Of note, NTR functions robustly whether fused to the N or C terminus of a fluorescent reporter, facilitating flexible transgene design (Curado et al., 2008; Pisharath and Parsons, 2009). In both studies, tissues regenerated after MTZ withdrawal, establishing the NTR/MTZ approach as a versatile, specific, inducible, and reversible tool for regeneration studies.

Unlike acute physical injury, NTR-mediated ablation induces apoptotic cell death and predominantly recruits macrophages rather than neutrophils (Stoddard et al., 2019). This is an important consideration, as the type of cell death shapes the regenerative response. In zebrafish, macrophages are not merely phagocytic responders but essential regulators of regeneration: they clear apoptotic debris, modulate the inflammatory milieu, and release factors that support appropriate tissue remodeling (Petrie et al., 2014; Bohaud et al., 2021).

This controlled context of NTR/MTZ ablation provides a platform for identifying the cells responsible for regeneration, a goal that can be achieved by pairing ablation with lineage tracing. For example, following targeted ablation of pancreatic β-cells, researchers used Cre-based lineage tracing to track the origins of regenerated endocrine cells. These studies revealed that Notch-responsive ductal cells called centroacinar cells act as facultative progenitors that delaminate from the ducts and replenish lost β-cells (Delaspre et al., 2015; Beer et al., 2016; Ghaye et al., 2015). A parallel strategy applied to hepatocyte ablation uncovered an analogous regenerative mechanism in the liver where Notch-responsive biliary epithelial cells (cholangiocytes) delaminate, dedifferentiate, proliferate, and redifferentiate into new hepatocytes (Choi et al., 2014; He et al., 2014). Combining single-cell RNA sequencing (scRNA-seq) of pancreatic ducts and hepatic ducts after β-cell/hepatocyte ablation has been used to map molecular mechanisms and identify intermediate progenitor states as new β-cells/hepatocytes are formed (Mi et al., 2023; Eski et al., 2025). This integrated paradigm of targeted ablation, Cre-based lineage tracing, and scRNA-seq provides a systematic framework for dissecting the mechanisms that drive tissue regeneration.

Combining Cre-based lineage tracing with NTR ablation can reveal the origins of regenerated cells. Another way to identify progenitors is to induce regeneration and then use NTR to ablate candidate progenitor populations, assessing whether regeneration is subsequently impaired. The Raible lab used two complementary ablation approaches to pinpoint the cells responsible for regeneration (Thomas and Raible, 2019). Neomycin, an aminoglycoside antibiotic, reliably ablates mature hair cells (Coffin et al., 2013), which normally regenerate fully. In parallel, the NTR/MTZ system was used to selectively ablate dorsoventral (DV) support cells, which were suspected to act as progenitors. When both the mature hair cells and DV support cells were eliminated, regeneration was dramatically impaired (Thomas and Raible, 2019). This dual-ablation strategy demonstrates another way the NTR/prodrug system can be used to identify the cell populations that contribute to regeneration.

The NTR/prodrug ablation system also lends itself well to modeling human diseases that are characterized by the specific and progressive loss of distinct cell populations. The core strengths of this chemogenetic approach include cell-type specificity and temporal control, which allows it to be a toolkit for recapitulating pathological events in vivo. This allows for the real-time dissection of disease initiation, progression, and complex cellular responses to injury. A diverse array of human pathologies has been modeled using NTR/MTZ in zebrafish, including chronic hyperglycemia (a symptom of diabetes) (Tucker et al., 2023), acute liver damage (Choi et al., 2014), and cardiac injury (Curado et al., 2007; Palencia-Desai et al., 2015; Apolínová et al., 2024). Here, we analyze selected models in greater detail, focusing on kidney disease, retinal degeneration, demyelinating disorders, and neurodegeneration (Figure 1 – orange boxes).

The NTR/MTZ ablation system provides a reproducible and scalable platform for functional screening in zebrafish, combining cell-type specificity, quantitative imaging, and compatibility with both chemical and genetic perturbations (Figure 2).

Figure 2

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The NTR/MTZ system is widely used for diverse applications, but its performance has varied between labs. Key issues include batch-to-batch and preparation variability of MTZ, the need for high MTZ doses (≈10 mM) that can cause off-target toxicity (e.g. developing brain [Lai et al., 2021], larval/adult intestine [Tucker et al., 2023]), and differential susceptibility of some cell types to ablation (Pisharath and Parsons, 2009). Because ablation rate depends on both NTR activity and MTZ dose, researchers have pursued three complementary strategies to improve reproducibility and experimental interpretation: (1) increase NTR expression, (2) engineer higher-activity NTR mutants, and (3) identify more efficacious prodrugs that achieve effective killing at lower, less toxic concentrations. These iterative improvements are aimed at mitigating previous limitations and expanding the range of feasible experimental paradigms and are discussed next.

1. Increase NTR expression: Strong, well-characterized promoters/enhancers (e.g. the zebrafish insulin promoter) (Pisharath et al., 2007) can drive high NTR expression, especially when present in multiple copies via Tol2-mediated transgenesis (Kalvaitytė et al., 2024). However, many cell-specific regulatory elements are weak, and maintaining multiple insertions is challenging and prone to genetic drift and intergenerational variability. An alternative is to use a bipartite system such as Gal4/UAS (Brand and Perrimon, 1993; Köster and Fraser, 2001), which can produce robust, amplified NTR expression even from a single genomic insertion. With this approach, a cell-specific promoter drives a Gal4 transactivator that binds UAS sites to strongly activate NTR transcription (Figure 3). For example, elements from the 14xUAS constructs of Köster and Fraser, 2001, were used to generate the transgenic line Tg(UAS-E1B:NTR-mCherry)^c264 (Pisharath and Parsons, 2009; Davison et al., 2007). These fish were distributed by the Zebrafish International Resource Center (ZIRC) and have been widely used by the zebrafish community: 10 of the 32 most-cited papers on zebrafish NTR ablation use this line (Supplementary file 1). A caveat is that Gal4/UAS DNA elements can be prone to epigenetic silencing, producing mosaic expression; the repetitive UAS contains multiple CpG sites susceptible to DNA methylation (Halpern et al., 2008; Goll et al., 2009). Silencing can be mitigated by using a less repetitive UAS (e.g. 4×) (Akitake et al., 2011) or by using the QF/QUAS bipartite system (derived from Neurospora) (Potter et al., 2010), which has been reported to show reduced silencing (Subedi et al., 2014) and has recently been adapted for NTR-based ablation (Figure 3, Lee et al., 2025; Lengyel et al., 2025).

2. Higher-activity NTR mutants: Substantial effort has gone into engineering more active NTRs; first driven by their promise as cancer ‘suicide-gene’ therapies (Guise et al., 2007) and later to improve NTR-based ablation in basic research (Mathias et al., 2014). Two research groups independently engineered the same three substitutions into the wild-type E. coli enzyme (now termed NTR1.0), creating more efficient versions they named epNTR and NTR1.1 (Guise et al., 2007; Mathias et al., 2014; Tabor et al., 2014). Cross-species screening identified a highly active NTR from Vibrio vulnificus. Using this enzyme as a scaffold, rational engineering yielded the second-generation variant NTR2.0, which exhibits a greater than 100-fold enhancement in activity over the original NTR1.0 (Sharrock et al., 2022).

   • The use of first-generation nitroreductase (NTR1) for chronic cell ablation was problematic, as the required 10 mM MTZ dose induces intestinal pathology and approaches the LD50 in zebrafish (Tucker et al., 2023). However, the more active NTR2.0 variant enables effective ablation with far lower, better-tolerated MTZ concentrations. To demonstrate this, Tucker et al. developed a zebrafish model expressing NTR2.0 specifically in pancreatic β-cells (Akitake et al., 2011). They found that efficient larval β-cell ablation required only 100 µM MTZ, a regimen that could be maintained for 10 days without ill effects. In stark contrast, the NTR1 system required a toxic 10 mM MTZ dose, which is lethal to larvae (independent of NTR) within 3 days. In adult fish, a regimen of 5 mM MTZ for 2 days followed by 2 weeks at 1 mM was completely tolerated by wild-type fish with no ill effects but induced sustained hyperglycemia and weight loss in NTR2.0-expressing fish. This established a powerful model for studying chronic diabetic consequences, such as retinopathy, nephropathy, and impaired wound healing.

   • This well-tolerated ablation paradigm now makes it possible to model a range of other chronic conditions, including neurodegenerative, renal, and muscular disorders. This capability, in turn, facilitates the study of long-term disease progression and the evaluation of new therapeutic interventions.

3. More efficacious prodrugs: MTZ efficacy can vary across suppliers and batches. To ensure consistency, it is recommended to prepare fresh MTZ solutions for experiments (Pisharath and Parsons, 2009; Tucker et al., 2023). To overcome MTZ’s limitations, alternative prodrugs like NFP have been tested. NFP is a more potent nitrofuran-based prodrug (Pisharath and Parsons, 2009; Tucker et al., 2023). However, its structural class is distinct from the nitroimidazole-based prodrugs for which NTR2.0 was specifically engineered (Sharrock et al., 2022). As a nitroimidazole prodrug, RNZ likely retains compatibility with newer NTR systems while offering significant practical advantages over MTZ, primarily its better potency (Teeters et al., 2025; Lai et al., 2021; Chen et al., 2023). For instance, in Tg(fabp10:mCherry-NTR1) fish, 2 mM RNZ achieved hepatocyte ablation comparable to 10 mM MTZ, a fivefold increase in potency (Chen et al., 2023). This pattern of higher efficacy was replicated in a macrophage model, where a fivefold lower RNZ dose was as effective as MTZ (Lai et al., 2021). Lai et al. also reported no bystander effects and demonstrated RNZ efficacy with the NTR1.1 variant. Recently, it has also been shown that RNZ functions with NTR2.0 to cause cell-specific ablation (Duan et al., 2025), although a direct comparison of RNZ versus MTZ with NTR2.0 has not been reported. Whether RNZ shows batch-to-batch variability similar to MTZ has not yet been reported. Given the potential for variability, it would be prudent for researchers to titrate each new batch of RNZ or, alternatively, adopt a dosing strategy that exceeds the minimum effective concentration to ensure consistent ablation results. Nonetheless, it is anticipated that the NTR2.0/RNZ combination will further lower the required prodrug concentrations and minimize off-target activity.

Figure 3

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Given this evolving landscape of prodrugs and enzymes, what are the critical factors a researcher must weigh when designing an NTR ablation experiment?

A successful ablation experiment using the NTR/prodrug system requires careful consideration of three key components: (1) transgenic strategy, (2) optimal NTR activity, and (3) appropriate controls. The optimal design depends on the biological question.

• For regeneration studies, aim for complete ablation to clearly assess neogenesis.

• For functional studies, partial ablation may be sufficient to reveal a phenotype.

1. Transgenic strategy:

   • Regulatory elements: Select regulatory elements that ensure precise tissue or cell-type specificity.

     • Discrete regulation: When a single promoter is insufficient to achieve the desired tissue specificity, use intersectional approaches (e.g. Cre/lox) to restrict expression (Zhong et al., 2019).

   • Fluorescent marker: Include an independent fluorescent marker (fusion or 2A reporter, Provost et al., 2007) to identify transgenic animals and confirm appropriate expression.

   • Positional effects: NTR transgenes, like any transgene, can exhibit positional effects (leakiness, mosaicism). To ensure reliable lines:

     • Screen multiple founders: Identify ≥5 F0 founders and ideally establish 5 independent F1 lines.

     • Compare stable F1 lines: Confirm that fluorescent-marker expression matches expected regulatory-element activity.

     • Prioritize F1 lines based on:

       • Mendelian transmission, indicating a single-site insertion.

       • Consistent, non-mosaic expression of the fluorescent marker, indicating uniform NTR expression in all intended cells.

       • Robust and reproducible expression, independent of whether the transgene is inherited maternally or paternally.

       • Reliable and consistent ablation of target cell.

2. NTR activity:

   • General principle: Strong NTR expression generally yields faster and more complete ablation (Sharrock et al., 2022; Tucker et al., 2023).

   • NTR variant: NTR2.0 is currently the most active NTR variant used in zebrafish and is recommended for future studies.

   • Prodrug choice: For most applications, RNZ is the recommended prodrug to start with, due to its higher efficacy and lower required dosing relative to MTZ, which can improve both ablation efficiency and experimental consistency.

   • Enhancing expression: If the promoter driving NTR2.0 is weak, amplify expression using binary systems such as Gal4/UAS or QF/QUAS (Figure 3, Lee et al., 2025; Davison et al., 2007; Lengyel et al., 2025).

3. Controls:

   • Validating cell death: To properly interpret ablation results, it is important to confirm that cell death occurred. Useful readouts include:

     • Apoptosis assays: TUNEL, cleaved caspase 3 immunostaining (Curado et al., 2008; Pisharath and Parsons, 2009).

     • Loss of fluorescent reporters (Curado et al., 2007; Pisharath et al., 2007; Pisharath and Parsons, 2009): If signal perdurance is a concern, use destabilized reporters to reduce fluorescence longevity (Walker et al., 2012; Wang et al., 2015).

   • Cell-death kinetics: As stressed cells may downregulate NTR and escape ablation, validating cell-death kinetics can be informative.

     • Use endpoint analysis (serial time-point fixation + apoptosis markers).

     • Or use cell-death biosensors, such as Hmgb1-GFP, which distinguishes necrosis (nuclear release) from apoptosis (nuclear retention) (Raucci et al., 2007; Scaffidi et al., 2002).

     • Example: In larvae co-expressing ins:mCherry-2A-NTR2.0 and ins:hmgb1-eGFP (Tucker et al., 2023; Parsons et al., 2009), high-dose MTZ (1 mM) induced apoptosis within 4 hr with complete β-cell loss by 24 hr; a low dose (10 μM) produced slower dynamics (Figure 4).

   • Negative controls

     • NTR transgene, no prodrug: Controls for effects of exogenous NTR expression.

     • No NTR transgene, prodrug: Controls for nonspecific MTZ/RNZ effects, including antimicrobial activity. For microbiome-associated studies, consider alternative ablation methods.

Figure 4

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Author details

1. Gha-Hyun J Kim

   1. Department of Clinical Pharmacy Practice, UC Irvine School of Pharmacy and Pharmaceutical Sciences, Irvine, United States
   2. Robert A. Mah Molecular Innovation Center, University of California, Irvine, Irvine, United States

   Contribution

   Resources, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9073-2034

2. Michael Parsons

   Department of Developmental and Cell Biology, School of Biological Sciences, Natural Sciences II, University of California, Irvine, Irvine, United States

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   mparson1@uci.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4046-1659

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