Prof. Dr. Joachim Wittbrodt
Prof. Dr. Joachim Wittbrodt
Im Neuenheimer Feld 230
Fon +49 6221 54-6499
Fax +49 6221 54-5639
jochen.wittbrodt AET cos.uni-heidelberg.de
Vertebrate eye and brain development and regeneration
The vertebrate eye is composed of neuroectodermal (optic cup) and surface ectodermal (lens, cornea) derivatives and it emerges from an epithelial Anlage by inductive interactions beginning al late gastrula stages. Under the influence of midline signaling during neurulation the single retina Anlage is split into two retinal primordia localized in the lateral wall of the forebrain.
Subsequent evagination of the primordia results in the formation of optic vesicles that differentiate to the seven cell types of the neural retina, the retinal pigmented epithelium and the optic stalk respectively. In anamniotes (fish, amphibia), the ciliary marginal zone (CMZ) of the neural retina contains a stem cell population that gives rise to all retinal cell types and facilitates life-long growth of the eye.
The lab is studying neuronal cell proliferation and differentiation in the developing, growing and regenerating eye and brain of fish (zebrafish, medaka) as model system. We are combining genetic, molecular and cell biological approaches with advanced imaging approaches to decipher the basic mechanisms that govern the balance of cell proliferation and differentiation in vivo. Special emphasis is given to follow the fate of proliferating and differentiating cells in the context of the fish retina and brain and to establish tools that allow visualizing the those processes in vivo. We take advantage of the life-long proliferation of retinal stem cells from the ciliary marginal zone (CMZ) that facilitates the continuous study of cells exiting the stem cell niche at the CMZ and their subsequent stereotypic differentiation.
We delineated factors involved in retinal growth and regeneration and the underlying transcriptional networks. A particular focus was on the role of retinal stem and progenitor cells and their role in establishing and maintaining the perfect shape of the eye which is fundamental for its functional homeostasis. We have shown that the neuroretina is creating shape out of itself via a programmed behavior of neuroretinal stem cells. The pigmented epithelium on the other side arises from the same stem cell niche and passively follows the lead (and shape) implemented by the action of the neuroretinal stem cells. Our computational model for retinal growth is complemented by functional insights originating from clonal gain and loss of function analyses of key players governing the activity of retinal stem and progenitor cells. We have employed stochastic activation of transcriptional modules that couple in vivo indicators with the gain or loss of function of key pathway components (e.g. of wnt signaling).
Our massive progress in Crispr/Cas technology was instrumental for the establishment of genetically validated conditional paradigms that now allow addressing the acute loss of key players (e.g. Rx genes). Those are of high interest since they appear to facilitate life-long growth of the retina in teleosts and their targeted inactivation has furthered our understanding of vertebrate retinal size control. Another striking feature of teleost eyes retinae is their apparently unlimited regenerative capacity. We carefully compared different species and took advantage of the loss of retinal regeneration in medaka (similar to human) to identify key factors that, when targeted to Mueller glia cells in the retina, reinstate the regenerative capacity.
Addressing the role of individual key genes in retinal development, growth and regeneration we initially focussed on the level of the population (tissue, organ). However, we soon realized that the function is only understood, when analysed on the level of the individual cell in the context of the population.
Future research goals
Jochen Wittbrodt is a member of the CellNetworks Cluster of Excellence, the collaboartive research centres SFB873 on stem cells wnt the SFB1324 and the HBIGS graduate school. Our work is supported by funds from a variety of public sources, including the DFG, the BMBF and the European Commission via the European Research Council ERC.