Development and regeneration of insulin-producing β cells: Diabetes is associated with a loss of β cells. The goal of the Parsons lab is to find therapeutic routes that can increase β-cell numbers and reverse a diabetic state. We utilize the zebrafish as a model system in order to expedite the discovery of the mechanisms that regulate the production of β cells from stem cells (neogenesis).
Zebrafish are an ideal system to study vertebrate embryogenesis, as they are genetically tractable and have transparent, externally developing embryos. Easy transgenesis allows specific cells and their behaviors to be visualized within living animals. Moreover, with their small size and high fecundity, the zebrafish represents the only tangible method to perform high-throughput chemical screening on a living, intact vertebrate organism. The Parsons lab was part of a collaborative effort that carried out the first truly high-throughput chemical screen on zebrafish larvae. What makes the zebrafish particularly compelling for research into β-cell neogenesis is that zebrafish pancreatic cells readily regenerate following damage. Consequently this model system provides two separate opportunities to experimentally manipulate and study β-cell neogenesis—namely, development and regeneration. We have identified the β-cell progenitor during both development and regeneration; these specialized cells are called centroacinar cells and are found in the pancreatic ducts of all vertebrates, including humans.
Building on this work, we are now discovering the molecular mechanisms that regulate the differentiation of centroacinar cells to β cells that occurs during zebrafish β-cell regeneration. This knowledge will reveal the pathways that should be pharmacologically induced in human tissues to facility human β-cell regeneration.
Current Lab Projects:
- Assessing the role of stem cells in pancreas regeneration.
- Using results from our chemical screens to improve protocols to make β cells in vitro from human embryonic stem cells.
- Using genomics-based approaches to examine the function of the transcription factor SOX9 in pancreatic progenitors.
- Testing the role of the peripheral nervous system and neuromodulators on β-cell development and biology.
- 2021 SOX9 modulates cancer biomarker and cilia genes in pancreatic cancer. Edelman HE, McClymont SA, Tucker TR, Pineda S, Beer RL, McCallion AS, Parsons MJ. Hum Mol Genet. 2021 Mar 9:ddab064. doi: 10.1093/hmg/ddab064. Online ahead of print
- 2020 Attenuating the EGFR-ERK-SOX9 axis promotes liver progenitor cell-mediated liver regeneration in zebrafish. So J, Kim M, Lee SH, Ko S, Lee DA, Park H, Azuma M, Parsons MJ, Prober D, Shin D. Hepatology. 2021 Apr;73(4):1494-1508. doi: 10.1002/hep.31437.PMID: 32602149
- 2017 Jagged directly induces liver and pancreas duct lineage in zebrafish. Zhang D, Gates K, Barske L, Wang G, Lancman J, Zeng X, Groff M, Wang K, Parsons MJ, Crump J and Dong, D. Nature Communications 8(1):769.
- 2016 Sox9b is a mediator of retinoic acid signaling restricting endocrine progenitor differentiation. Huang W, Beer RL, Delaspre F, Wang G, Edelman HE, Park H, Azuma M and Parsons MJ. Developmental Biology 418(1): 28-39.
- 2016 Centroacinar cells: At the center of pancreas regeneration (review). Beer RL, Parsons MJ and Rovira MC. Developmental Biology 413(1): 8-15. Front cover.
- 2015 Centroacinar cells are progenitors that contribute to endocrine pancreas regeneration. Delaspre F, Beer RL, Rovira M, Huang W, Wang G, Gee S, Vitery MC, Wheelan SJ, and Parsons MJ. Diabetes 64(10): 3499-3509.
- 2015 First quantitative high-throughput screen in a vertebrate model system: repurposing drugs for increased β-cell mass. Wang G, Rajpurohit SK, Delaspre F, Walker SL, White DT, Ceasrine A, Kuruvilla R, Li R, Shim JS, Liu JO, Parsons MJ,* Mumm JS.* eLife 4:e08261 *Joint work
- 2015 Fate mapping of ptf1a-expressing cells during pancreatic organogenesis and regeneration in zebrafish. Wang YJ, Park JT, Parsons MJ and Leach SD. Developmental Dynamics 244(6): 724-735.
- 2014 Differential in vivo tumorigenicity of diverse KRAS mutations in vertebrate pancreas: A comprehensive survey. Park JT, Johnson N, Liu S, Levesque M, Wang YJ, Ho H, Huso D, Maitra A, Parsons MJ, Prescott JD, Leach SD. Oncogene 34(21): 2801-2806.
- 2014 Retinoic acid plays an evolutionarily conserved and biphasic role in pancreas development. Huang W, Wang G, Delaspre F, Vitery MD, Beer RL, Parsons MJ. Developmental Biology 394(1): 83-93.
- 2014 Adoption of the Q transcriptional regulatory system for zebrafish transgenesis. Subedi A, Macurak M, Gee ST, Monge E, Goll MG, Potter CJ, Parsons MJ, Halpern ME. Methods 66(3): 433-440.
- 2013 Aldh1-expressing endocrine progenitor cells regulate secondary islet formation in larval zebrafish pancreas. Matsuda H, Parsons MJ, Leach SD. PLoS One. 17; 8(9):e74350. doi: 10.1371/journal.pone.0074350.
- 2012 Zebrafish sox9b is crucial for hepatopancreatic duct development and pancreatic endocrine cell regeneration. Manfroid I, Ghaye A, Naye F, Detry N, Palm S, Pan L, Ma TP, Huang W, Rovira M, Martial JA, Parsons MJ, Moens CB, Voz ML and Peers B. Developmental Biology 366(2): 268-278.
- 2012 Automated Reporter Quantification in vivo: High-throughput Screening Method for Reporter-based Assays in Zebrafish. Walker SL, Ariga J, Mathias JR, Coothankandaswamy V, Xie X, Distel M, Köster RW, Parsons MJ, Bhalla KN, Saxena MT, and Mumm JS. PLoS One 7:e29916.
- 2011 Chemical screen identifies FDA approved drugs and target pathways that induce precocious β-cell differentiation. Rovira M, Huang W, Yusuff S, Shim JS, Ferrante AA, Liu JO and Parsons MJ. Proc Natl. Acad Sci USA 108 (48):19264-9.
- 2011 Genetic inducible fate mapping in larval zebrafish reveals origins of adult insulin producing β-cells. Wang Y, Rovira M, Yusuff S, Huang W and Parsons MJ. Development 138 (4): 609-617.
- 2009 Notch-responsive progenitors initiate the secondary transition in larval zebrafish pancreas. Parsons MJ, Pisharath H, Yusuff S, Moore JC, Siekmann AF, Lawson N, and Leach SD. Mechanisms of Development 126(10): 898-912.
- 2009 Regeneration of the Pancreas in Adult Zebrafish. Moss JB, Koustubhan P, Greenman M, Parsons MJ, Walter I, Moss LG. Diabetes 58 (8): 1844-1851.
- 2009 Nitroreductase-mediated cell ablation in transgenic zebrafish embryos. Pisharath H, Parsons MJ. Book chapter in Zebrafish: Methods and Protocols (Methods in Molecular Biology) 546: 133-143.
- 2007 Targeted ablation of beta cells in the embryonic zebrafish pancreas using E.coli nitroreductase. Pisharath H, Rhee J, Swanson M, Leach SD and Parsons MJ. Mechanisms of Development 124(3): 218-227.