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Aprea J.,Research Center and Cluster of Excellence for Regenerative Therapies | Prenninger S.,Research Center and Cluster of Excellence for Regenerative Therapies | Dori M.,Research Center and Cluster of Excellence for Regenerative Therapies | Ghosh T.,University Pierre and Marie Curie | And 11 more authors.
EMBO Journal | Year: 2013

Transcriptome analysis of somatic stem cells and their progeny is fundamental to identify new factors controlling proliferation versus differentiation during tissue formation. Here, we generated a combinatorial, fluorescent reporter mouse line to isolate proliferating neural stem cells, differentiating progenitors and newborn neurons that coexist as intermingled cell populations during brain development. Transcriptome sequencing revealed numerous novel long non-coding (lnc)RNAs and uncharacterized protein-coding transcripts identifying the signature of neurogenic commitment. Importantly, most lncRNAs overlapped neurogenic genes and shared with them a nearly identical expression pattern suggesting that lncRNAs control corticogenesis by tuning the expression of nearby cell fate determinants. We assessed the power of our approach by manipulating lncRNAs and protein-coding transcripts with no function in corticogenesis reported to date. This led to several evident phenotypes in neurogenic commitment and neuronal survival, indicating that our study provides a remarkably high number of uncharacterized transcripts with hitherto unsuspected roles in brain development. Finally, we focussed on one lncRNA, Miat, whose manipulation was found to trigger pleiotropic effects on brain development and aberrant splicing of Wnt7b. Hence, our study suggests that lncRNA-mediated alternative splicing of cell fate determinants controls stem-cell commitment during neurogenesis. © 2013 European Molecular Biology Organization.


PubMed | Deep Sequencing Group, Research Center and Cluster of Excellence for Regenerative Therapies and Max Planck Institute for Physics
Type: Journal Article | Journal: Neurogenesis (Austin, Tex.) | Year: 2016

Long non-coding (lnc)RNAs play key roles in many biological processes. Elucidating the function of lncRNAs in cell type specification during organ development requires knowledge about their expression in individual progenitor types rather than in whole tissues. To achieve this during cortical development, we used a dual-reporter mouse line to isolate coexisting proliferating neural stem cells, differentiating neurogenic progenitors and newborn neurons and assessed the expression of lncRNAs by paired-end, high-throughput sequencing. We identified 379 genomic loci encoding novel lncRNAs and performed a comprehensive assessment of cell-specific expression patterns for all, annotated and novel, lncRNAs described to date. Our study provides a powerful new resource for studying these elusive transcripts during stem cell commitment and neurogenesis.


Aprea J.,Research Center and Cluster of Excellence for Regenerative Therapies | Nonaka-Kinoshita M.,Research Center and Cluster of Excellence for Regenerative Therapies | Nonaka-Kinoshita M.,Astellas Pharma Inc. | Calegari F.,Research Center and Cluster of Excellence for Regenerative Therapies
Genesis | Year: 2014

SUMMARY: Neurod1 is a transcription factor involved in several developmental programs of the gastrointestinal tract, pancreas, neurosensory, and central nervous system. In the brain, Neurod1 has been shown to be essential for neurogenesis as well as migration, maturation, and survival of newborn neurons during development and adulthood. Interestingly, Neurod1 expression is maintained in a subset of fully mature neurons where its function remains unclear. To study the role of Neurod1, systems are required that allow the temporal and spatial genetic manipulation of Neurod1-expressing cells. To this aim, we have generated four Neurod1-CreERT2 mouse lines in which CreERT2 expression, although at different levels, is restricted within areas of physiological Neurod1 expression and Neurod1 positive cells. In particular, the different levels of CreERT2 expression in different mouse lines offers the opportunity to select the one that is more suited for a given experimental approach. Hence, our Neurod1-CreERT2 lines provide valuable new tools for the manipulation of newborn neurons during development and adulthood as well as for studying the subpopulation of mature neurons that retain Neurod1 expression throughout life. In this context, we here report that Neurod1 is not only expressed in immature newborn neurons of the adult hippocampus, as already described, but also in fully mature granule cells of the dentate gyrus. © 2014 Wiley Periodicals, Inc.


PubMed | Research Center and Cluster of Excellence for Regenerative Therapies
Type: Journal Article | Journal: Genesis (New York, N.Y. : 2000) | Year: 2014

Neurod1 is a transcription factor involved in several developmental programs of the gastrointestinal tract, pancreas, neurosensory, and central nervous system. In the brain, Neurod1 has been shown to be essential for neurogenesis as well as migration, maturation, and survival of newborn neurons during development and adulthood. Interestingly, Neurod1 expression is maintained in a subset of fully mature neurons where its function remains unclear. To study the role of Neurod1, systems are required that allow the temporal and spatial genetic manipulation of Neurod1-expressing cells. To this aim, we have generated four Neurod1-CreER(T2) mouse lines in which CreER(T2) expression, although at different levels, is restricted within areas of physiological Neurod1 expression and Neurod1 positive cells. In particular, the different levels of CreER(T2) expression in different mouse lines offers the opportunity to select the one that is more suited for a given experimental approach. Hence, our Neurod1-CreER(T2) lines provide valuable new tools for the manipulation of newborn neurons during development and adulthood as well as for studying the subpopulation of mature neurons that retain Neurod1 expression throughout life. In this context, we here report that Neurod1 is not only expressed in immature newborn neurons of the adult hippocampus, as already described, but also in fully mature granule cells of the dentate gyrus.


PubMed | Research Center and Cluster of Excellence for Regenerative Therapies
Type: Journal Article | Journal: The EMBO journal | Year: 2013

Transcriptome analysis of somatic stem cells and their progeny is fundamental to identify new factors controlling proliferation versus differentiation during tissue formation. Here, we generated a combinatorial, fluorescent reporter mouse line to isolate proliferating neural stem cells, differentiating progenitors and newborn neurons that coexist as intermingled cell populations during brain development. Transcriptome sequencing revealed numerous novel long non-coding (lnc)RNAs and uncharacterized protein-coding transcripts identifying the signature of neurogenic commitment. Importantly, most lncRNAs overlapped neurogenic genes and shared with them a nearly identical expression pattern suggesting that lncRNAs control corticogenesis by tuning the expression of nearby cell fate determinants. We assessed the power of our approach by manipulating lncRNAs and protein-coding transcripts with no function in corticogenesis reported to date. This led to several evident phenotypes in neurogenic commitment and neuronal survival, indicating that our study provides a remarkably high number of uncharacterized transcripts with hitherto unsuspected roles in brain development. Finally, we focussed on one lncRNA, Miat, whose manipulation was found to trigger pleiotropic effects on brain development and aberrant splicing of Wnt7b. Hence, our study suggests that lncRNA-mediated alternative splicing of cell fate determinants controls stem-cell commitment during neurogenesis.

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