Molecular mechanisms of stem cell plasticity and regenerative neurogenesis in adult zebrafish brain
Previous and Current Research
The brains of aging humans are prone to neurodegenerative disorders and we are unable to counteract neuronal loss by regenerating lost cells. Patients with neurodegenerative conditions progressively loose neurons yet cannot form new neurons that would replace the lost ones. However, in nature, several vertebrates such as zebrafish bear a widespread regenerative ability that includes replenishment of neurons in the adult central nervous system due to the neurogenic activity of the progenitor cells. We have recently identified that this regenerative ability in fish requires turning on special molecular programs of the neural progenitor cells that in the end make regenerative neurogenesis possible. These findings suggest that regenerating organisms such as zebrafish could use special molecular programs to modulate the plasticity of the neural stem cells and enable restoration of compromised neural tissues. Hypothetically, these programs might also underlie the disparity between the regenerative capacities of zebrafish brain and mammalian brains. Therefore, we might consider neurodegenerative diseases of humans to some degree also as “stem cell diseases”. The main motivation for my independent research group will be to understand what it takes in terms of molecular programs for zebrafish brain to regenerate itself after neurodegeneration, and which parts of those relevant molecular programs are missing in mammalian brains. These findings will be important in terms of contributing to the efforts to design therapeutic approaches to circumvent the detrimental consequences of neurodegeneration in human brains and open up new avenues for regenerative medicine.
Future Projects and Goals
- To learn from zebrafish how to enable the adult brains to better cope with neurodegenerative disease and regenerate
- To identify the molecular mechanisms of neural stem cell plasticity in adult zebrafish brain after various types of tissue damage or physiological stimulations
Methodological and Technical Expertise
- Zebrafish genetics
- Cerebroventricular microinjection (CVMI)
- Gene expression profiling and functional analyses
- Immunohistochemical detection and microscopy
Tincer, G., Mashkaryan, V., Bhattarai, P., Kizil, C.
Neural stem/progenitor cells in Alzheimer’s disease.
The Yale Journal of Biology and Medicine, 89(1), 23–35. (2016)
Kizil C, Küchler B, Yan JJ, Ozhan G, Moro E, Argenton F, Brand M, Weidinger G, Antos CL.
Simplet/Fam53b is required for Wnt signal transduction by regulating β-catenin nuclear localization.
Development. 141(18):3529–39. (2014)
Kizil C, Kyritsis N, Dudczig S, Kroehne V, Freudenreich D, Kaslin J, Brand M.
Regenerative neurogenesis from neural progenitor cells requires injury-induced expression of Gata3.
Developmental Cell, 23(6):1230–7 (2012)
Kyritsis N, Kizil C, Zocher S, Kroehne V, Kaslin J, Freudenreich D, Iltzsche A, Brand M.
Acute Inflammation Initiates the Regenerative Response in the Adult Zebrafish Brain.
Science, 338(6112):1353–6 (2012)
Kizil C, Dudczig S, Kyritsis N, Machate A, Blaesche J, Kroehne V, Brand M.
The chemokine receptor cxcr5 regulates the regenerative neurogenesis response in the adult zebrafish brain.
Neural Development 7:27 (2012)