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Caren Norden
Cell Migration and Lamination in the Developing Retina
Previous and current research
The retina is a lateral extension of the central nervous system and has the advantage of being particularly accesible for imaging approaches. It is a highly fascinating structure that bears a high level of complexity. It consists of six types of neuron and one type of glia cells that interconnect with each other leading to precise wiring of the visual system. Three conditions have to be fulfilled for correct lamination of these different cell types to ensure accurate architecture and a fully functioning eye for the animal:
The vertebrate retina, and especially the optically transparent zebrafish retina, is an outstanding model system for imaging and manipulating neuronal development in vivo. As a lateral extension of the CNS on the surface of the zebrafish embryo, the retina provides a system accessible to experimental manipulation, and is allows for high-resolution in embryo microscopy. It is a fascinating structure that bears a high level of complexity which consists of six types of neuron and one type of glia cells that interconnect with each other leading to precise wiring of the visual system. The three main questions I want to ask in my lab are the following:
What triggers progenitor cells to leave the cell cycle and become neurons of different kinds?
How do neurons, once born, reach their final destination within the retina? What are the underlying migratory cues and mechanisms?
How do different neurons in the retina form the right amount of axons and dendrites and polarize them into the correct directions?
One focus of my research has been investigating mechanics and kinetics of Interkinetic Nuclear Migration (IKNM). IKNM is a hallmark of pseudostratisfied neuroepithelia for which the retina is an example. So far IKNM has mainly been compared to an elevator movement: Mitosis and cytokinesis occur at the apical side of the epithelium, during G1 nuclei exhibit a smooth transition towards the basal side of the cell, undergo S-phase there and during G2 migrate back towards the apical side. My recent studies challenge this view as I found that IKNM in the zebrafish retina is in fact best described by stochastic motions of nuclei that are punctuated with phases of directed movement around mitosis. Additionally, despite the fact that cells feature a highly polarized stable microtubule cytoskeleton it seems to be an actomyosin-based mechanism that is important for both rapid directed as well as stochastic movements while microtubules might play a role in fine tuning nuclear position (Norden et al. 2009).
Artistic Depiction of the proliferative epithelium. Nuclei are in light blue, actin accumulations are in green, centrosomes at the apical side are in pink. Drawn by William A Harris .
Future prospects and goals
Based on the work on IKNM, there are several subsequent questions I would like to follow up with my new group. These include:
How are the different modes of motion linked to cell cycle phases and what are the implications on cell fate? Are the stochastic movements we observe cell autonomous or do they derive from collective dynamics of the epithelium? What is the molecular trigger for the switch from stochastic to persistent rapid movement and is there a spatial accumulation of actomyosin activity?
Another focus of research will deal with the question how neuronal migration is achieved for the different cell types. Two general types of migration occur in the retina: Retinal Ganglion Cells and Bipolar Cells undergo somal translocation of the nucleus and other organelles with apical and basal processes still attached to the respective lamina before these processes are detached once the soma reached the cells final position. In contrast Amacrine and Horizontal Cells undergo free migration to reach their final destination. I want to understand the differences and similarities of these two migratory modes on a mechanistic and molecular level. Additionally, I would like to perform studies to understand how final lamination and neuronal polarization is realized with axons and dendrites forming at the exact right positions and in the exact right orientation for different cell types.
State of the art microscopy will be used to investigate these questions. These include conventional confocal and spinning disk confocal microscopy, laser ablation and two photon techniques. To reach our goals we will take advantage of the immense possibilities that come with the light microscopy facilities at the institute. Data analysis will involve quantitative measurements of movements and kinetics, which should lead to fascinating insights in the development, and structure formation of the vertebrate retina. These findings will most likely help to understand events in other parts of the brain.
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Selected publications
Norden C, Young S, Link BA, Harris WA.: Actomyosin is the main driver of interkinetic nuclear migration in the retina. Cell. 2009 Sep 18;138(6):1195-208.
Mendoza M, Norden C, Durrer K, Rauter H, Uhlmann F, Barral Y., (2009): A mechanism for chromosome segregation sensing by the NoCut checkpoint. Nat Cell Biol. 2009 Apr;11(4):477-83.
Norden, C., Mendoza M., Dobbelaere, J., Kotwaliwale, C, Biggins, S. and Y. Barral, (2006): The NoCut pathway links completion of cytokinesis to spindle midzone function to prevent chromosome breakage. Cell. 2006 Apr 7;125(1):85-98
Wisco D, Anderson ED, Chang MC, Norden, C, Boiko T, Fölsch H, Winckler B.: Uncovering multiple axonal targeting pathways in hippocampal neurons. J Cell Biol. 2003 Sep 29;162(7):1317-28.