Retinal Ganglion Cells (RGCs) collect visual information from the neural retina in the eye and convey it to the visual cortex of the brain. In healthy people, this information is transmitted along the optic nerve, which is composed mainly of axons formed from the cell bodies of RGCs. Progressive degeneration of the optic nerve from diseases such as glaucoma, diabetic retinopathy and Leber hereditary optic neuropathy interrupts this information flow and eventually leads to RGC death and permanent blindness. We currently lack effective treatments to prevent RGC death or enable axon regeneration.
Targeted drug delivery and gene therapies are promising approaches for preventing RGC death. One therapeutic approach might be, for example, to reprogram resident RGCs to acquire new identities that protect them. Clinical application of these therapies imposes (1) to identify proteins that are associated with nerve cell survival and/or protection of their axons (2) to understand how these proteins function in physiological condition, in normal and disease animal models (3) to effectively and safely manipulate such molecular factors (by drug delivery or gene therapy) to ultimately restore vision in human.
Our research on the atoh7 transcription factor – a gene associated with congenital optic nerve hypoplasia – has established Zebrafish as model paradigm whereby we can carry out these investigations. We employ gene editing (e.g. CRISPR-Cas systems) and pharmacological approaches to probe candidate molecules for their role in RGC maturation and survival. With advanced live 3D microscopy we assess in real time how retinal nerve cells behave as the candidate key/reprogramming molecules become active in the living organism.
We aim to uncover novel potential drug targets that we will subsequently test in primary cultures of adult porcine and/or human retina, for their beneficial role in preserving nerve cell function and reversing neurodegenerative processes in mammals.
Amongst potential players as neuroprotective molecules of the brain are the crystallins, previously thought as lens-specific proteins. These heat shock proteins become up-regulated in many ocular tissues upon hypoxia, damage or disease but molecular and functional insights remain elusive. One study that we carry out in collaboration with the Ophthalmology clinic at Heidelberg University (headed by Prof G U Auffarth) uses human lens epithelial cells as in vitro platform to investigate these dynamic cellular processes and their implications for ocular neuroprotection.
Exciting research has demonstrated that even differentiated resident nerve cells of the adult can be reprogrammed to take on new identities. This opens another window of opportunity for effective therapeutic treatment of RGCs. Adding or inducing production of “degenerative-resistant” proteins characteristic of closely related types of retinal cells could save these RGCs. Conversely, more RGCs could be made from neighboring neurons, which could still use the existing cellular "pathfinding" as a guide, for example for growing an axon towards the visual cortex.
As a prerequisite to assess these possibilities, we identified specific RGCs and other nerve cells with common developmental-origin from retinal progenitor cells. These lineally related cells or “sister cells” might be more amenable to reprogramming because of their shared genetic signatures. We now aim to pinpoint molecular factors with roles in the subtype identity specification, maturation and survival of RGCs and their sister cells. Alongside, our ambitious goal is to study these cell types for their intrinsic abilities to de-differentiate, undergo self-renewal (asymmetric) divisions, and/or activate RGC developmental programs in the adult retina of Zebrafish and mammals.
Motivated scientists at any level are more than welcome to apply. Substantial help for research and raising funds (fellowships etc.) will be provided
- Gerd U Auffarth, Universitäts-Augenklinik, University of Heidelberg
- Fritz Hengerer, Universitäts-Augenklinik, University of Heidelberg
- Saadettin Sel, Universitäts-Augenklinik, University of Heidelberg
- Elfriede Friedmann, Institute of Applied Mathematics, University of Heidelberg
- Patricia Jusuf, ARMI Australian Regenerative Medicine Institute, Monash University
- Mirana Ramialison, ARMI Australian Regenerative Medicine Institute, Monash University
- Mónica Lamas Gregori, Departamento de Farmacobiología, CINVESTAV
- Matthias Carl, CIBIO, Trento University
- Carlo A. Beretta, CellNetworks Math-Clinic, University of Heidelberg
- Filippo del Bene, Institut Curie - Centre de Recherche, Paris
Cepero Malo M, Duchemin AL, Guglielmi L, Patzel E, Sel S, Auffarth GU, Carl M, Poggi L. The Zebrafish Anillin-eGFP Reporter Marks Late Dividing Retinal Precursors and Stem Cells Entering Neuronal Lineages. PLoS One. 2017 Jan 20;12(1):e0170356. doi: 10.1371/journal.pone.0170356. eCollection 2017.
Sel S, Patzel E, Poggi L, Kaiser D, Kalinski T, Schicht M, Paulsen F, Nass N. Temporal and spatial expression pattern of Nnat during mouse eye development. Gene Expr Patterns. 2017 Jan;23-24:7-12. doi: 10.1016/j.gep.2016.12.002. Epub 2016 Dec 27.
Paolini A, Duchemin AL, Albadri S, Patzel E, Bornhorst D, González Avalos P, Lemke S, Machate A, Brand M, Sel S, Di Donato V, Del Bene F, Zolessi FR, Ramialison M, Poggi L. Asymmetric inheritance of the apical domain and self-renewal of retinal ganglion cell progenitors depend on Anillin function. Development. 2015 Mar 1;142(5):832-9. doi: 10.1242/dev.118612. Epub 2015 Feb 5.
Hüsken U, Stickney HL, Gestri G, Bianco IH, Faro A, Young RM, Roussigne M, Hawkins TA, Beretta CA, Brinkmann I, Paolini A, Jacinto R, Albadri S, Dreosti E, Tsalavouta M, Schwarz Q, Cavodeassi F, Barth AK, Wen L, Zhang B, Blader P, Yaksi E, Poggi L, Zigman M, Lin S, Wilson SW, Carl M., Tcf7l2 is required for left-right asymmetric differentiation of habenular neurons. Curr Biol. 2014 Oct 6;24(19):2217-27. doi: 10.1016/j.cub.2014.08.006. Epub 2014 Sep 4.
Scholpp S, Poggi L, Zigman M.Brain on the stage - spotlight on nervous system development in zebrafish: EMBO practical course, KIT, Sept. 2013. Neural Dev. 2013 Dec 19;8:23. doi: 10.1186/1749-8104-8-23. Review.
Jusuf PR, Harris WA, Poggi L. Imaging retinal progenitor lineages in developing zebrafish embryos. Cold Spring Harb Protoc. 2013 Mar 1;2013(3). pii: pdb.prot073544. doi: 10.1101/pdb.prot073544. Review.
Jusuf PR, Albadri S, Paolini A, Currie PD, Argenton F, Higashijima S, Harris WA, Poggi L. Biasing amacrine subtypes in the Atoh7 lineage through expression of Barhl2.. J Neurosci. 2012 Oct 3;32(40):13929-44. doi: 10.1523/JNEUROSCI.2073-12.2012.
Schuhmacher LN, Albadri S, Ramialison M, Poggi L. Evolutionary relationships and diversification of barhl genes within retinal cell lineages. BMC Evol Biol. 2011 Nov 21;11:340. doi: 10.1186/1471-2148-11-340.
Randlett O, Poggi L, Zolessi FR, Harris WA. The oriented emergence of axons from retinal ganglion cells is directed by laminin contact in vivo. Neuron. 2011 Apr 28;70(2):266-80. doi: 10.1016/j.neuron.2011.03.013.
Jusuf PR, Almeida AD, Randlett O, Joubin K, Poggi L, Harris WA. Origin and determination of inhibitory cell lineages in the vertebrate retina. J Neurosci. 2011 Feb 16;31(7):2549-62. doi: 10.1523/JNEUROSCI.4713-10.2011.
Zolessi FR, Poggi L, Wilkinson CJ, Chien CB, Harris WA. Polarization and orientation of retinal ganglion cells in vivo. Neural Dev. 2006 Oct 13;1:2.
Cayouette M, Poggi L, Harris WA. Lineage in the vertebrate retina. Trends Neurosci. 2006 Oct;29(10):563-70. Epub 2006 Aug 21. Review.
Poggi L, Vitorino M, Masai I, Harris WA. Influences on neural lineage and mode of division in the zebrafish retina in vivo. J Cell Biol. 2005 Dec 19;171(6):991-9.
Poggi L, Zolessi FR, Harris WA.Time-lapse analysis of retinal differentiation. Curr Opin Cell Biol. 2005 Dec;17(6):676-81. Epub 2005 Oct 13. Review.