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Transcriptome sequencing during mouse brain development identifies long non‐coding RNAs functionally involved in neurogenic commitment

Julieta Aprea, Silvia Prenninger, Martina Dori, Tanay Ghosh, Laura Sebastian Monasor, Elke Wessendorf, Sara Zocher, Simone Massalini, Dimitra Alexopoulou, Mathias Lesche, Andreas Dahl, Matthias Groszer, Michael Hiller, Federico Calegari

Author Affiliations

  1. Julieta Aprea1,,
  2. Silvia Prenninger1,,
  3. Martina Dori1,
  4. Tanay Ghosh2,
  5. Laura Sebastian Monasor1,
  6. Elke Wessendorf1,
  7. Sara Zocher1,
  8. Simone Massalini1,
  9. Dimitra Alexopoulou1,
  10. Mathias Lesche1,
  11. Andreas Dahl1,
  12. Matthias Groszer2,
  13. Michael Hiller3,4 and
  14. Federico Calegari*,1
  1. 1 DFG–Research Center and Cluster of Excellence for Regenerative Therapies, Dresden, Germany
  2. 2 Institut du Fer à Moulin, INSERM UMR‐S 839, Université Pierre and Marie Curie, Paris, France
  3. 3 Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
  4. 4 Max Planck Institute for the Physics of Complex Systems, Dresden, Germany
  1. *Corresponding author. CRTD, Technische Universität Dresden, Fetscherstrasse 105, Dresden 01307, Germany. Tel.:+49 0 351 45882204; Fax:+49 0 351 45882209; E-mail: federico.calegari{at}crt-dresden.de

Abstract

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.

  • Received June 6, 2013.
  • Accepted October 23, 2013.

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