Abstract
During neurogenesis, generation, migration and integration of the correct numbers of each neuron sub-type depends on complex molecular interactions in space and time. MicroRNAs represent a key control level allowing the flexibility and stability needed for this process. Insight into the role of this regulatory pathway in the brain is still limited. We performed a sequential experimental approach using postnatal olfactory bulb neurogenesis in mice, starting from global expression analyses to the investigation of functional interactions between defined microRNAs and their targets. Deep sequencing of small RNAs extracted from defined compartments of the postnatal neurogenic system demonstrated that the miR-200 family is specifically induced during late neuronal differentiation stages. Using in vivo strategies we interfered with the entire miR-200 family in loss- and gain-of-function settings, showing a role of miR-200 in neuronal maturation. This function is mediated by targeting the transcription factor Zeb2. Interestingly, so far functional interaction between miR-200 and Zeb2 has been exclusively reported in cancer or cultured stem cells. Our data demonstrate that this regulatory interaction is also active during normal neurogenesis.
Highlights
Generate large amounts of neuronal precursors that, after their amplification migrate tangentially within the rostral migratory stream (RMS) into the olfactory bulb (OB)
We generated a complete profile of microRNA expression, based on deep sequencing of small RNAs, in the principal compartments of this neurogenic system. Using this unique dataset we identified a family of microRNAs, the miR-200 family, that is expressed at late neurogenic stages but absent from immature differentiation intermediates
We investigated the expression pattern and dynamics of microRNA expression in the OB neurogenic system through the miRNome analysis of defined compartments
Summary
Generate large amounts of neuronal precursors that, after their amplification migrate tangentially within the rostral migratory stream (RMS) into the OB Once arrived in their target structure they migrate radially into the granular and glomerular layers where they differentiate into interneurons that use GABA, dopamine or glutamate as their neurotransmitters[17,18]. We generated a complete profile of microRNA expression, based on deep sequencing of small RNAs, in the principal compartments of this neurogenic system. Using this unique dataset we identified a family of microRNAs, the miR-200 family, that is expressed at late neurogenic stages but absent from immature differentiation intermediates. We show that miR-200 microRNAs function in this context by targeting the zinc-finger transcription factor Zeb[2]
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