Department of Biological Sciences

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Collection and identification of Plasmodiophora brassicae pathotypes from western Canada in 2021-2023
(2025) Storfie, Emilee; Manolii, Victor P.; Aigu, Yoann; Botero-Ramirez, Andrea; Harding, Michael W.; Hwang, Sheau-Fang; Strelkov, Stephen E.
Clubroot disease, caused by Plasmodiophora brassicae, is a major threat to canola (Brassica napus) production in the Canadian Prairies. One of the most effective clubroot management strategies is the deployment of clubroot-resistant cultivars. ‘First-generation’ resistant cultivars, with resistance derived from B. napus cv. ‘Mendel’, provided farmers with an initial line of defence. However, the emergence of more virulent pathotypes of P. brassicae has led to an increasing number of cases where these novel pathotypes overcome resistance, resulting in severe clubroot symptoms in previously resistant cultivars. In this study, 206 field isolates of the pathogen were collected between 2021 and 2023 from Alberta (194 isolates), Saskatchewan (eight isolates) and Manitoba (four isolates). Pathotype designations were determined using the Canadian Clubroot Differential (CCD) set, leading to the identification of 31 unique pathotypes. Among these were 10 novel ‘resistance-breaking’ pathotypes, designated as 1D, 1E, 1G, 3F, 3I, 3J, 5D, 6F, 8K and 9G, along with pathotypes 1H and 3G, still controlled by first-generation resistance. The novel pathotype 5D, virulent on ‘Mendel’, represents the first instance of a resistance-breaking pathotype in Saskatchewan. Despite the large number of pathotypes detected, pathotypes 3A (25%), 3D (17%) and 3H (15%) remain the most prevalent in Alberta, consistent with previous years. Other notable pathotypes, including 8E, 8N, 8P and 9E, continue to be detected, albeit at lower frequencies (4–8%). The rapid diversification of pathotypes and the spread of P. brassicae in the canola growing regions of Canada underscore the importance of continued surveillance.
Effect of clubroot (Plasmodiophora brassicae) on yield of canola (Brassica napus)
(2022) Botero-Ramírez, Andrea; Hwang, Sheau-Fang; Strelkov, Stephen E.
Clubroot, caused by Plasmodiophora brassicae, is a major disease of canola (Brassica napus). This study evaluated the effect of clubroot development on the yield of this crop under field and greenhouse conditions. Three canola cultivars, ‘45H31’ (susceptible), ‘45H29’ (1st-generation resistance) and ‘CS2000’ (2nd-generation resistance), were inoculated with different quantities of P. brassicae inoculum and monitored for yield, pods per plant and 1000-grain weight. The field experiment was conducted over 2 years in biosecure clubroot nurseries inoculated with pathotype 5X or a mix of pathotypes 5X and 3H at 5 × 104, 5 × 106 and 5 × 108 resting spores per plant. In the greenhouse experiment, plants were inoculated with pathotypes 5X, 3H or a mixture of both at 1 × 103, 1 × 104 and 1 × 106 resting spores per plant. In both the field and greenhouse, clubroot incidence and disease severity index (DSI) increased along with inoculum concentration; the highest levels of disease were observed in the susceptible cultivar, while the lowest levels were found in ‘45H29.’ Yield, pods per plant and 1000-grain weight decreased as the DSI increased in all cultivars. Yield was affected by DSI and cultivar but not pathotype. Regression analysis indicated that under greenhouse conditions, an increment of 1% in DSI resulted in a decrease of 0.49% in yield; under field conditions, this percentage was reduced to 0.26%. While the rate of yield reduction was similar among cultivars, overall yield loss was lower in the resistant hosts, as they developed less disease.
Pancreatic ductal cell heterogeneity: insights into the potential for β-cell regeneration in diabetes
(2025) Britt, Madelaine; Abdilmasih , Nicholas; Rezanejad, Habib
Diabetes mellitus is a significant and fast-growing health problem worldwide. Cost, donor shortages, and immune rejection limit current treatment strategies. While considerable progress has been made in creating β-cells in vitro with remarkable morphological and functional resemblance to those in primary pancreatic islets, exploring alternative sources for β-cell replacement is crucial. With adult pancreatic stem cells still not conclusively identified, researchers focus their attention on heterogeneity within pancreatic ductal epithelial cells, exploring these cells as a potential source of progenitor cells for pancreatic regeneration and β-cell formation. Recent studies using techniques such as fluorescence-activated cell sorting, immunostaining and single cell RNA-sequencing have identified ductal cell heterogeneity with several subpopulations of ductal cells with progenitor-like properties and their capacity for differentiation into insulin producing cells. Here, we have reviewed the most recent studies on pancreatic ductal cell subpopulations that offer insights into potential stem-cell populations to form β-cells in diabetes treatment.
Synteny enabled upgrade of the Galapagos giant tortoise genome improves inferences of runs of homozygosity
(2025) Jensen, Evelyn L.; Marchisio, Chiara; Ochoa, Alexander; Gray, Rachel; Parra, Vanessa; Miller, Joshua M.; Çilingir, F. Gözde; Caccone, Adalgisa
The utility and importance of whole-genome sequences are recognized across various fields, including evolution and conservation. However, for some taxa, like extinct species, using methods to generate contiguous genomes that rely on high-quality DNA is impossible. In such cases, an alternative may be to employ synteny-based methods using a genome from a closely related taxon to generate more complete genomes. Here we update the reference genome for the Pinta Island Galapagos giant tortoise (Chelonoidis abingdonii) without conducting additional sequencing through rescaffolding against the most closely related chromosome-level genome assembly, the Aldabra giant tortoise (Aldabrachelys gigantea). This effort resulted in a much more contiguous genome, CheloAbing_2.0, with an N50 that is two orders of magnitude longer and large reductions inL50 and the number of gaps. We then examined the impact of the CheloAbing_2.0 genome on estimates of runs of homozygosity (ROH) using genome resequencing data from 37 individual Galapagos giant tortoises from the 13 extant lineages to test the mechanisms by which a fragmented assembly may over- or underestimate the number and extent of ROH. The use of CheloAbing_2.0 resulted in individual estimates of inbreeding, including ROH proportion (F ROH), number (N ROH), and cumulative length (S ROH), that were statistically different from those derived from the earlier genome assembly. This improved genome will serve as a resource for future efforts focusing on the ecology, evolution, and conservation of this species group. More broadly, our results highlight that synteny-based scaffolding is promising for generating contiguous genomes without needing additional data types.
Sexual size and shape dimorphism are consistent with predictions that both natural and sexual selection are driving the evolution of sexual dimorphism in Mormon crickets, Anabrus simplex
(2025) Judge, Kevin; Demma, Stacy R.; Robson, Laura J.; Lorch, Patrick D.; Vinyard, Christopher J.; Gwynne, Darryl T.
Selection can be a powerful force causing morphological adaptation in populations. We tested predictions about the role of both natural and sexual selection in shaping morphology in the Mormon cricket, Anabrus simplex, a species with two population types that differ in their ecological conditions. Solitary populations are characterized by low densities, non-migratory individuals, and typical mating roles (males compete for access to choosy females), whereas gregarious populations are characterized by high densities, migratory behaviour, reversed mating roles, and widespread cannibalism. We collected individuals from both solitary and gregarious populations – characterized by their behaviour and not morphology – and measured several morphological traits. We transformed these traits to shape variables by dividing each measurement by a geometric mean of several metric dimensions representing body size. We tested for population type and sex differences in size and shape variables, and we tested for population type differences in several sex-limited shape variables. We also used discriminant function analysis to test whether a previously enigmatic population, found to be genetically like gregarious populations, but exhibiting many aspects of solitary population behaviour, was morphologically more like solitary or gregarious populations. Our analysis was used to determine the minimum number of measurements needed to assign specimens to the correct population type.
Plasmodiophora brassicae inoculum density and spatial patterns at the field level and relation to soil characteristics
(2021) Botero-Ramirez, Andrea; Hwang, Sheau-Fang; Strelkov, Stephen E.
Clubroot, caused by Plasmodiophora brassicae, is an important soilborne disease of the Brassicaceae. Knowledge of the spatial dynamics of P. brassicae at the field level and the influence of soil properties on pathogen spatial patterns can improve understanding of clubroot epidemiology and management. To study the spatial patterns of P. brassicae inoculum density and their relationship to different soil properties, four clubroot-infested fields in central Alberta, Canada, were sampled in 2017 and 2019, and P. brassicae inoculum density, soil pH, and boron, calcium, and magnesium concentrations were quantified. Spatial autocorrelation of the inoculum density was estimated for each of the fields in both years with the Moran’s I and semi-variograms. A Bayesian hierarchical spatial approach was used to model the relationship between P. brassicae inoculum density and the soil parameters. Patchiness of the pathogen was detected, with most patches located at the field edges and adjacent to the entrance. Infested patches grew in size from 2017 to 2019, with an average increase in diameter of 221.3 m and with this growth determined by the maximum inoculum density and active dispersal methods such as movement by machinery and wind. Soil pH, boron, calcium, and magnesium concentrations were not found to have an important effect on the inoculum density of P. brassicae.
Soil, climate, and management practices associated with the prevalence of clubroot in Colombia
(2022) Botero-Ramirez, Andrea; Padilla-Huertas, Fabián Leonardo; García, Celsa
Clubroot disease caused by Plasmodiophora brassicae is a major constraint for cruciferous crops in Colombia; however, information regarding its spread and the relationship between environmental and crop management practices with its occurrence in the country is scarce. This research established clubroot prevalence in the main cruciferous productive areas in Colombia and the relation of its occurrence with crop management practices, soil, and climatic characteristics. In total, 127 fields were visited along eight departments. Clubroot infestation was determined either by direct inspection of roots of host plants for clubroot symptoms or by report of previous observation of the disease symptoms by the farmers. Soil samples were collected for physical and chemical analysis, climatic information was obtained, and farmers were surveyed on the management practices of the production systems. The survey confirmed the presence of the disease in 53.6% of the visited fields. The only department where the disease symptoms were not observed nor reported was Nariño. A negative correlation was found between the disease occurrence and the content of aluminum in the soil, the number of days with rain per year, and the cultivation of clubroot-resistant hybrids. Moreover, a positive correlation was observed with the inclusion of cruciferous crops in the rotation scheme, the effective cation exchange capacity of the soil, soil pH, and the content of phosphorus, calcium, boron, and copper in the soil.
The occurrence of clubroot in Colombia and its relationship with climate and agronomic practices
(2022) Botero-Ramirez, Andrea; Padilla-Huertas, Fabián Leonardo; Strelkov, Stephen E.; García-Dominguez, Celsa
Clubroot, caused by Plasmodiophora brassicae, is a major disease of cruciferous crops in Colombia. Limited information is available, however, regarding its distribution or epidemiology in this country. The objectives of this study were to determine the occurrence of clubroot in the main regions of Colombia where cruciferous crops are grown, and to examine the relationship between pathogen inoculum density and the likelihood of field infestation with crop management practices and climatic information. In total, 127 fields were surveyed across eight departments, the pathogen inoculum density was estimated, climatic information was obtained, and farmers were surveyed on their crop management practices. More than half (53.7%) of the fields visited were found to be clubroot-infested and pathogen DNA was detected in 91.3% of the surveyed fields. The only department where clubroot symptoms were not observed was Nariño. In infested fields, P. brassicae inoculum density varied between 3 × 102 and 1 × 106 resting spores per gram of soil, with the highest inoculum density observed in Norte de Santander. All other departments had comparable spore loads. Inoculum density positively affected the likelihood of infestation of a field, and both spore loads and infestations were positively affected by the average temperature.
Optimizing clubroot management and the role of canola cultivar mixtures
(2024) Botero-Ramirez, Andrea; Kirk, Brennon; Strelkov, Stephen E.
The sustainable cultivation of canola is under threat from clubroot disease (Plasmodiophora brassicae). The pathogen’s resting spores can survive in the soil for extended periods, complicating disease management. Therefore, effective clubroot control requires a combination of tactics that provide multiple layers of protection. Management strategies have focused on pathogen avoidance and reducing disease levels in infested fields. The sanitation of machinery and field equipment remains the most effective method for preventing the pathogen’s introduction into non-infested fields. For disease reduction, crop rotation, liming, chemical control, and host resistance are commonly employed, with the use of clubroot-resistant cultivars being the most effective to date. However, resistance breakdown has been observed within four years of the introduction of new cultivars, jeopardizing the long-term effectiveness of this approach. A promising yet underexplored strategy is the use of cultivar mixtures. This approach leverages mechanisms such as the dilution effect, the barrier effect, induced resistance, disruptive selection, and the compensatory effect to control the disease. Cultivar mixtures have the potential to reduce the impact of clubroot on canola production while preserving pathogen population structure, thereby minimizing the likelihood of resistance breakdown. Given its potential, further research into cultivar mixtures as a management strategy for clubroot disease is warranted.
Nature kids: out and about
(2024) Haines, Jessica A.
How well do you know Alberta’s waterfowl? Test your identification skills on a few of our species by matching the photos with the descriptions of these wonderful waterfowl below.
Impacts of garlic mustard (Alliaria petiolata, Brassicaceae) invasion on oribatid mites in urban forest soils vary with the size of the invaded patch
(2024) Flaherty, Leah; Hills, Melissa; Giacobbo, Victoria; Kuczmarski, Paige; Momborquette, Morgan; Lumley, Lisa
Investment in non-native species management should be informed by knowledge of impact, including on native biodiversity and ecosystem function. Oribatid soil mites may be useful to evaluate the impacts of plant invasions since they are bioindicators of disturbance and soil ecosystem health. Still, more research is needed to characterize their responses to plant invasion, especially at the species level. Our objective was to determine the effect of invasion of urban forest understories by an allelopathic weed (garlic mustard, Alliaria petiolata (Brassicaceae)) on belowground oribatid mite species and communities. At two sites in central Alberta (Canada), over two years, we examined adult oribatid (≥ 300 µm) community assemblages, species richness, evenness, diversity, and abundance in plots invaded with garlic mustard and uninvaded plots with native vegetation. Environmental covariates known to be associated with soil invertebrate communities were also evaluated. Results suggest that the spatial extent of the garlic mustard invasion (patch area) mediates its impact on oribatid mite communities. However, there were no community-level impacts when considering invasion as binary (garlic mustard vs. native vegetation). Garlic mustard patch area influenced oribatid community composition and was positively related to species richness and several abundance metrics. The oribatid species we observed benefiting from garlic mustard invasion have been previously associated with disturbed soils. The mechanisms driving these patterns need more research, but we hypothesize they may relate to patch-specific resident times. Site was also a dominant factor influencing oribatid mite communities, and impacts of year, litter depth, and canopy cover were also detected at the species and/or community level. These findings contribute to our understanding of the impact of an invasive weed on bioindicating soil mite communities and species and highlight the importance of considering invasion context, including spatial extent when evaluating the impacts of invasive species on belowground invertebrate communities.
Microsporidia in fish
(2014) Kent, Michael L.; Shaw, Ross W.; Sanders, Justin L.; Weiss, Louis M.; Becnel, James J.
The importance of microsporidia in captive fishes continues to increase with the continued dramatic increase in finfish aquaculture. Most microsporidia of fish are transmitted without intermediate hosts, and hence, cultured fish are particularly susceptible to microsporidian infections due to high stocking densities, compared to their wild counterparts. There are several examples of microsporidia causing disease in cultured food fishes. Early investigations of fish microsporidia included some observations of host response. Several drugs have been used to treat microsporidian infections in fish, mostly on an experimental basis. Most reports of successful treatments were with fumagillin. This drug is an antimicrobial agent developed for treating Nosema apis infections in honeybees and is the most widely used drug used for treating microsporidiosis in fishes.
Galapagos giant tortoise trafficking case demonstrates the utility and applications of long-term comprehensive genetic monitoring
(2023) Quinzin, Maud C.; Bishop, Anusha P.; Miller, Joshua M.; Poulakakis, Nikos; Tapia, W.; Torres-Rojo, F.; Sevilla, C.; Caccone, Adalgisa
Illegal Wildlife Trade (IWT) is a cause for global concern as pressure stemming from IWT threatens wild species and can even lead to extinction. Galapagos giant tortoises (Chelonoidis sp.) are a group of threatened species protected under CITES, which forbids their import–export for international trade; however, IWT of this group persists. In this study, we describe the use of two extensive genetic repositories of mitochondrial and nuclear microsatellite markers for Galapagos giant tortoises to identify an unsuspected source of trafficked juvenile tortoises. Our genetic analyses, together with morphological and captive-born registry data, provide evidence that the smuggled juveniles were from two breeding centers dedicated toward conservation located on the Galapagos islands of San Cristobal and Isabela. This is the first documentation of smuggled tortoises being taken from breeding centers rather than the wild. The findings from our genetic analysis provided key evidence that enabled legal investigation. This case demonstrates the importance of the comprehensive genetic characterization of Galapagos giant tortoises and the suitability of standard genetic markers for identifying the species and islands of origin of trafficked animals. We also discuss the efficacy, adequacy, and reach of existing measures against IWT. Overall, this case illustrates an important application of long-term and comprehensive genetic repositories of endangered species and the crucial role of collaborations among academic laboratories maintaining those repositories, local practitioners responsible for species protection, and the bodies that implement and enforce antitrafficking regulations.
Leveraging genomic load estimates to optimize captive breeding programmes
(2024) Jensen, Evelyn L.; Gray, Rachel; Miller, Joshua M.
Rapid biodiversity loss threatens many species with extinction. Captive populations of species of conservation concern (such as those housed in zoos and dedicated breeding centres) act as an insurance should wild populations go extinct or need supplemental individuals to boost populations. Limited resources mean that captive populations are almost always small and started from few founding individuals. As a result, captive populations require careful management to minimize negative genetic impacts, with decisions about which individuals to breed together often guided by the principle of minimizing relatedness. Typically this strategy aims to retain 90% of genetic diversity over 200 years (Soulé et al., Zoo Biology, 1986, 5, 101), but it has a weakness in that it does not directly manage for genetic load. In this issue of MolecularEcology Resources, Speak et al. (Molecular Ecology Resources, 2024, e13967) present a novel proof-of-concept study for taking this next step and incorporating estimates of individual genetic load into the planning of captive breeding, using an approach that is likely to be widely applicable to many captive populations.
Generation of pancreatic ductal organoids and whole-mount immunostaining of intact organoids
(2018) Rezanejad, Habib; Hollister Lock, Jennifer; Sullivan, Brooke A.; Bonner-Weir, Susan
Traditionally, studies of cells and tissues have been performed on isolated primary cells or immortalized cell lines by culturing them in 2D culture dishes or flasks. However, a caveat regarding 2D culture is that the cells poorly recapitulate their in vivo counterparts, mainly due to a lack of 3D cell-cell and cell–extracellular matrix interactions. In recent years, the development of in vitro organoids as 3D culture has gained substantial attention as a model to study different tissues. In adults, pancreatic ductal cells are considered as a source of stem or progenitor cells, so developing new methods to study ductal cells would be useful. Here, we provide a protocol to isolate mouse pancreatic ductal cells and a cost-effective protocol to generate 3D organoid structures from such ductal cells. Additionally, we have devised a protocol for immunostaining of intact whole organoids without sectioning.
Pancreatic ductal cell heterogeneity: insights into the potential for β-cell regeneration in diabetes
(2025) Britt, Madelaine; Abdilmasih, Nicholas; Rezanejad, Habib
Diabetes mellitus is a significant and fast-growing health problem worldwide. Cost, donor shortages, and immune rejection limit current treatment strategies. While considerable progress has been made in creating β-cells in vitro with remarkable morphological and functional resemblance to those in primary pancreatic islets, exploring alternative sources for β-cell replacement is crucial. With adult pancreatic stem cells still not conclusively identified, researchers focus their attention on heterogeneity within pancreatic ductal epithelial cells, exploring these cells as a potential source of progenitor cells for pancreatic regeneration and β-cell formation. Recent studies using techniques such as fluorescence-activated cell sorting, immunostaining and single cell RNA-sequencing have identified ductal cell heterogeneity with several subpopulations of ductal cells with progenitor-like properties and their capacity for differentiation into insulin producing cells. Here, we have reviewed the most recent studies on pancreatic ductal cell subpopulations that offer insights into potential stem-cell populations to form β-cells in diabetes treatment.
In vitro differentiation of adipose-tissue-derived mesenchymal stem cells into neural retinal cells through expression of human PAX6 (5a) gene
(2014) Rezanejad, Habib; Soheili, Zahra-soheila; Haddad, Farhang; Matin, Maryam M.; Samiei, Shahram; Manafi, Ali; Ahmadieh, Hamid
The neural retina is subjected to various degenerative conditions. Regenerative stem-cell-based therapy holds great promise for treating severe retinal degeneration diseases, although many drawbacks remain to be overcome. One important problem is to gain authentically differentiated cells for replacement. Paired box 6 protein (5a) (PAX6 (5a)) is a highly conserved master control gene that has an essential role in the development of the vertebrate visual system. Human adipose-tissue-derived stem cell (hADSC) isolation was performed by using fat tissues and was confirmed by the differentiation potential of the cells into adipocytes and osteocytes and by their surface marker profile. The coding region of the human PAX6 (5a) gene isoform was cloned and lentiviral particles were propagated in HEK293T. The differentiation of hADSCs into retinal cells was characterized by morphological characteristics, quantitative real-time reverse transcription plus the polymerase chain reaction (qPCR) and immunocytochemistry (ICC) for some retinal cell-specific and retinal pigmented epithelial (RPE) cell-specific markers. hADSCs were successfully isolated. Flow cytometric analysis of surface markers indicated the high purity (97 %) of isolated hADSCs. After 30 h of post-transduction, cells gradually showed the characteristic morphology of neuronal cells and small axon-like processes emerged. qPCR and ICC confirmed the differentiation of some neural retinal cells and RPE cells. Thus, PAX6 (5a) transcription factor expression, together with medium supplemented with fibronectin, is able to induce the differentiation of hADSCs into retinal progenitors, RPE cells and photoreceptors.
Heterogeneity of SOX9 and HNF1β in pancreatic ducts is dynamic
(2018) Rezanejad, Habib; Ouziel-Yahalom, Limor; Keyzer, Charlotte A.; Sullivan, Brooke A.; Hollister-Lock, Jennifer; Li, Wan-Chun; Guo, Lili; Deng, Shaopeng; Lei, Ji; Markmann, James; Bonner-Weir, Susan
Pancreatic duct epithelial cells have been suggested as a source of progenitors for pancreatic growth and regeneration. However, genetic lineage-tracing experiments with pancreatic duct-specific Cre expression have given conflicting results. Using immunofluorescence and flow cytometry, we show heterogeneous expression of both HNF1β and SOX9 in adult human and murine ductal epithelium. Their expression was dynamic and diminished significantly after induced replication. Purified pancreatic duct cells formed organoid structures in 3D culture, and heterogeneity of expression of Hnf1β and Sox9 was maintained even after passaging. Using antibodies against a second cell surface molecule CD51 (human) or CD24 (mouse), we could isolate living subpopulations of duct cells enriched for high or low expression of HNF1β and SOX9. Only the CD24high (Hnfβ high/Sox9 high) subpopulation was able to form organoids.
Reinforcing one-carbon metabolism via folic acid/Folr1 promotes β-cell differentiation
(2021) Karampelias, Christos; Rezanejad, Habib; Rosko, Mandy; Duan, Likun; Lu, Jing; Pazzagli, Laura; Bertolino, Philippe; Cesta, Carolyn E.; Liu, Xiaojing; Korbutt, Gregory S.; Andersson, Olov
Diabetes can be caused by an insufficiency in β-cell mass. Here, we performed a genetic screen in a zebrafish model of β-cell loss to identify pathways promoting β-cell regeneration. We found that both folate receptor 1 (folr1) overexpression and treatment with folinic acid, stimulated β-cell differentiation in zebrafish. Treatment with folinic acid also stimulated β-cell differentiation in cultures of neonatal pig islets, showing that the effect could be translated to a mammalian system. In both zebrafish and neonatal pig islets, the increased β-cell differentiation originated from ductal cells. Mechanistically, comparative metabolomic analysis of zebrafish with/without β-cell ablation and with/without folinic acid treatment indicated β-cell regeneration could be attributed to changes in the pyrimidine, carnitine, and serine pathways. Overall, our results suggest evolutionarily conserved and previously unknown roles for folic acid and one-carbon metabolism in the generation of β-cells.
MNK2 deficiency potentiates β-cell regeneration via translational regulation
(2022) Karampelias, Christos; Watt, Kathleen; Mattsson, Charlotte L.; Ruiz, Angel Fernández; Rezanejad, Habib; Mi, Jiarui; Liu, Xiaojing; Chu, Lianhe; Locasale, Jason W.; Korbutt, Gregory S.; Rovira, Meritxell; Larsson, Ola; Andersson, Olov
Regenerating pancreatic β-cells is a potential curative approach for diabetes. We previously identified the small molecule CID661578 as a potent inducer of β-cell regeneration, but its target and mechanism of action have remained unknown. We now screened 257 million yeast clones and determined that CID661578 targets MAP kinase-interacting serine/threonine kinase 2 (MNK2), an interaction we genetically validated in vivo. CID661578 increased β-cell neogenesis from ductal cells in zebrafish, neonatal pig islet aggregates and human pancreatic ductal organoids. Mechanistically, we found that CID661578 boosts protein synthesis and regeneration by blocking MNK2 from binding eIF4G in the translation initiation complex at the mRNA cap. Unexpectedly, this blocking activity augmented eIF4E phosphorylation depending on MNK1 and bolstered the interaction between eIF4E and eIF4G, which is necessary for both hypertranslation and β-cell regeneration. Taken together, our findings demonstrate a targetable role of MNK2-controlled translation in β-cell regeneration, a role that warrants further investigation in diabetes.

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