Jörg Hackermüller & Mike Karl

LncRNA Functions in Retina Development & Regeneration.



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1st. Financiation

In mammals regeneration is limited to specific tissues – the mechanisms are unclear. Recent discoveries suggest that this restriction could be overcome by induction of defined regenerative programs. Neuronal regeneration in the mammalian central nervous system (CNS) is highly limited and cannot significantly compensate cell loss. The retina is part of the CNS and its degeneration a leading cause for vision loss. A key question is, whether cells surviving neurodegenerative diseases harbor any regenerative capacity that might be utilized therapeutically. The retina may serve as a unique model system to identify and overcome mechanisms limiting its regeneration in mammals. In fish Müller glia cells (MG) acting as adult stem cells regenerate retinal neurons. In mammals, the retina harbors no physiological adult neurogenesis, but contains MG. These do not naturally regenerate neurons but phenotypically change in most pathological conditions analogously to injury response in other brain regions often called reactive gliosis. A major question we pursue is whether gliosis is an aberrant or incomplete regenerative response or an independent entity. We provided the first evidence that specific stimulation enables MG derived regeneration in adult mice in vivo. Now we present preliminary data that neurons can more efficiently regenerate from juvenile compared to adult MG. We thus observe an age-dependent restriction in MG proliferation (Fig.1) and reprogramming to gain stem cell competence suggesting underlying regulated mechanisms are limiting regeneration.

Furthermore, retinal cells derive from multipotent progenitors (RPC), which during embryonic development switch from proliferating to differentiating. Mechanisms underlying gain, maintenance and loss of RPC stem cell and neurogenic function are not completely solved but seem to involve a balance of epigenetic modifications.

We hypothesize that the switch between stemness and differentiation in RPC and the age-dependent restriction of the MG regenerative potential (Fig.2), i.e. to gain stemness in MG are the results of common mechanisms controlling stem cell properties; possibly involving differentially expressed lncRNAs.

Key technologies:

- RNAseq
- ChIPseq
- Bioinformatic analyses of high throughput data
- Structural bioinformatics of RNA
- mouse /human pluripotent stem cells
- pluripotent stem cell derived retina organoidogenesis
- manipulation of neural stem cells, glia & neurons (viral, electroporation)

Last Publications

- Hackermüller J, Reiche K, Otto C, Hösler N, Blumert C, Brocke-Heidrich C, Böhlig L, Nitsche A, Kasack K, Ahnert P, Krupp W, Engeland K, Stadler PF, Horn F. Cell cycle, oncogenic and tumor suppressor pathways regulate numerous long and macro non-protein coding RNAs. Genome Biology 15:R48. 2014.

- Reiche K, Kasack K, Schreiber S, Lüders T, Due EU, Naume, Riis M, Kristensen VN, Horn F, Børresen-Dale A, Hackermuller J, Baumbusch LO. Long non-coding RNAs differentially expressed between normal versus primary breast tumor tissues disclose converse changes to breast cancer-related protein-coding genes. PLOS ONE. 9(9):e106076. 2014.

- Boll K, Reiche K, Kasack K, Mörbt N, Kretzschmar AK, Tomm JM, Verhaegh G, Schalken J, von Bergen M, Horn F, Hackermüller J. MiR-130a, miR-203, and miR-205 jointly repress key oncogenic pathways and are downregulated in prostate carcinoma. Oncogene. 32:277-85. 2013.

- P53 is required for the developmental restriction in Müller glial proliferation in mouse retina. Ueki Y, Karl MO, Sudar S, Pollak J, Taylor RJ, Loeffler K, Wilken MS, Reardon S, Reh TA. Glia. 2012 Oct;60(10):1579-89. doi: 10.1002/glia.22377. Epub 2012 Jul 6.

- Karl, M.O., and Reh, T.A. (2012). Studying the generation of regenerated retinal neuron from Muller glia in the mouse eye. Methods in molecular biology 884, 213-227.

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