Project Details
Projekt
LncRNA Functions in Retina Development & Regeneration.
Applicants
Dr. Jörg Hackermüller; Dr. Mike O. Karl
Subject Area
Developmental Neurobiology
Molecular Biology and Physiology of Neurons and Glial Cells
Molecular Biology and Physiology of Neurons and Glial Cells
Term
from 2014 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 255324742
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 and reprogramming to gain stem cell competence suggesting underlying regulated mechanisms are limiting regeneration. Retinal cells derive from multipotent progenitors (RPC). During embryonic development RPC switch from proliferating to differentiating. Mechanisms underlying gain, maintenance and loss of RPC function are unclear but seem to involve a balance of epigenetic modifications. In neuronal progenitors interactions of DNA methylation and differential modification of Polycomb targets, particularly of PRC2, restrict multipotency and contribute to cell fate determination. PRC2 is guided by long and short ncRNAs and directly affects cell fate in retina. We hypothesize that (i) the switch between stemness and differentiation in RPC and the age-dependent restriction of the regenerative potential, i.e. to gain stemness in MG are the results of common mechanisms controlling stem cell properties; (ii) this control occurs at the epigenetic level involving PCR2, and (iii) during this process differentially expressed lncRNAs guide PCR2 to sites of action in the genome. We therefore propose to investigate the transcriptomes of proliferating versus differentiating RPCs, MG from damaged versus control juvenile and adult retina. We particularly aim at identifying lncRNAs that associate with stemness in RPC and in juvenile MG but not in adult MG upon damage. We intersect these with lncRNAs binding PRC2. Selected candidates will be profiled in their role in retinal regeneration and genomic binding sites alongside with PRC2.
DFG Programme
Priority Programmes
