|Department Affiliations||Ophthalmology (primary), Neuroscience, Institute of Genetic Medicine|
|SOM Address||4015 Smith Building|
Our lab studies the development and repair of the nervous system applying unique advantages afforded by the zebrafish system including intravital imaging, robust regeneration, and large-scale screening. To broaden the study of cellular regeneration, we developed a targeted cell ablation technique that can be used to induce apoptosis in any genetically-definable cell type (Mathias et al. 2012; White & Mumm 2013). When applied in zebrafish, this methodology opens several potent avenues of investigation:
- Novel cell-specific regeneration paradigms and associated degenerative disease models;
- Neuron/circuit function, linking neuronal subtypes and circuits to discrete behaviors and percepts;
- Neural stem cell niche, composition of and cross-talk within interactive cellular networks of repair;
- Alternative modes of regeneration, ‘developmental’ versus injury-specific repair mechanisms, and;
- Large-scale genetic & chemical screens, systematic discovery of mechanisms regulating regeneration.
We are particularly interested in roles the innate immune system plays in controlling neuronal regeneration. Intravital imaging, cell function, and chemical genetics approaches recently defined retinal microglia as key regulators of retinal repair (White et al., 2017). In addition, two ongoing discovery-based initiatives are particularly exciting: ‘Forward’ and ‘reverse’ genetic screens are being used to establish regeneration-deficient mutants, thereby identifying genes required for the replacement of specific neuronal subtypes. Mutant lines also provide a valuable resource for chemical screens aimed at identifying drugs that stimulate regeneration. Accordingly, we developed a complementary High-throughput Phenotypic Screening (HPS) system for quantifying reporter activity, e.g., cellular regeneration kinetics, in living zebrafish (Walker et al. 2012; Wang et al. 2015; White et al. 2016). Key advantages of this approach are: 1) Scale, true high-throughput rates are enabled by an automated robotics platform (i.e., >50,000 fish per day) and, 2) Versatility, adaptable to a myriad of reporter-based assay and accommodating fish from embryonic to juvenile stages. Recently, in collaboration with Dr. Valeria Canto-Soler, we have adapted our cell ablation and HPS methodologies to human organoids – i.e., stem cell-derived ‘mini-retinas’ grown in a dish. Cross-species comparative studies will be used to reveal common mechanisms regulating the regenerative potential of conserved neural stem cell niches; insights needed to develop therapies for stimulating dormant repair mechanisms in the human CNS.
Mathias J, Saxena M, Mumm J (2012). Advances in zebrafish chemical screening technologies. Future Medicinal Chemistry, 4: 1811-1822.
Walker S*, Ariga J*, Mathias J, Coothankandaswamy V, Xie X, Distel M, Koster R, Parsons M, Bhalla K, Saxena M, Mumm J (2012). Automated reporter quantification in vivo: high-throughput screening method for reporter-based assays in zebrafish. PLoS ONE, 7:e29916. *equal contribution.
Wang G, Rajpurohit S, Delaspre F, Walker F, White D, Ceasrine A, Kuruvilla R, Li R, Shim J, Liu J, Parsons M#, Mumm J# (2015). First quantitative high-throughput screen in zebrafish identifies novel pathways for increasing pancreatic β-cell mass. eLife, Jul 28;4. doi: 10.7554/eLife.08261.
White D, Mumm J (2013).The nitroreductase system of inducible targeted ablation facilitates cell-specific regenerative studies in zebrafish. Methods, 62: 232-40.
White D*, Eroglu A*, Wang G*, Zhang L, Sengupta S, Ding D, Rajpurohit S, Walker S, Ji H, Qian J, Mumm J (2016). ARQiv-HTS, a versatile whole-organism screening platform enabling in vivo drug discovery at high-throughput rates. Nature Protocol, 11: 2432–2453. *equal contribution.
White D, Sengupta S, Mumm J (2017). Immunomodulation-accelerated retinal regeneration via innate immune system regulation of the retinal neural stem cell niche in zebrafish. Proceedings of the National Academy of Sciences USA, 2017, in press.