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Neural stem cells (NSCs) are restricted to few neurogenic niches in the otherwise gliogenic environment in the adult mammalian brain. It is thus important to understand the molecular mechanisms regulating their maintenance and neurogenic lineage progression as a prime paradigm of how neurons can be generated in an adult mammalian brain. Our genome-wide expression analysis of NSCs from the adult subependymal zone (SEZ) revealed the phenomenon of neurogenic priming, i.e. expression of neurogenic fate determinants at low level with no detectable protein levels in the NSCs. This low level expression thus primes the NSCs towards neurogenesis, but still allows multipotency and does not prematurely differentiate these cells into neuronal progenitors that have much higher mRNA and protein levels. Here we aim to examine the molecular basis a) maintaining this priming state and b) raising expression and protein levels when neuroblasts emerge from the NSCs. Our analysis of the transcriptome of NSCs and their progeny identified several microRNAs (miRNAs) as candidate for the former process (a) and several long non-coding RNAs (lncRNAs) as candidates for (b). We propose to test in this proposal our model in which specific miRNAs maintain the low expression of neurogenic fate determinants, thereby acting as guardians of premature up-regulation of neurogenic fate determinants and fine-tuning of neurogenesis. Taken together we believe that the proposed model of non-coding RNA function for adult stem cell lineage priming regulating multipotency and lineage progression may have broader relevance for adult stem cells beyond the nervous system and hence be highly relevant to examine within the framework of this priority program.
Falk S., Bugeon S., Ninkovic J., Pilz G.-A., Postiglione M.-P., Cremer H., Knoblich J.A. and Götz M. (2017) Time-Specific Effects of Spindle Positioning on Embryonic Progenitor Pool Composition and Adult Neural Stem Cell Seeding, Neuron - See here.
Ramesh V.*, Bayam E.*, Cernilogar F.M., Bonapace I.M, Schulze M., Riemenschneider M.J., Schotta G., Götz M. (2016) Loss of Uhrf1 in neural stem cells leads to activation of retroviral elements and delayed neurodegeneration. Genes & Development 30, 2199-2212. IF:10.798
Falkner S.*, Grade S.*, Dimou L., Conzelmann K.-K., Tobias Bonhoeffer, Götz M.* and Hübener M.* (2016) Transplanted embryonic neurons integrate into adult neocortical circuits. Nature 539, 248-253. Highlighted by Grealish and Parmar, Cell Stem Cell 19, 679-680. IF 42.351
Calzolari F., Michel J., Baumgart E., Theis F., Götz M.* and Ninkovic J.*(2015) Fast clonal expansion and limited neural stem cell self-renewal in the adult subependymal zone. Nature Neuroscience 18, 490 - 494
Barbosa J., Sanchez Gonzalez R., Di Giaimo R., Baumgart E.V., Theis, F.J., Götz M. and Ninkovic J. (2015) Live imaging of adult neural stem cell behavior in the intact and injured zebrafish brain. Science 348, 789 – 793.