miR-7a regulation of Pax6 controls spatial origin of forebrain dopaminergic neurons

Abstract

In the postnatal and adult mouse forebrain, a mosaic of spatially separated neural stem cells along the lateral wall of the ventricles generates defined types of olfactory bulb neurons. To understand the mechanisms underlying the regionalization of the stem cell pool, we focused on the transcription factor Pax6, a determinant of the dopaminergic phenotype in this system. We found that, although Pax6 mRNA was transcribed widely along the ventricular walls, Pax6 protein was restricted to the dorsal aspect. This dorsal restriction was a result of inhibition of protein expression by miR-7a, a microRNA (miRNA) that was expressed in a gradient opposing Pax6. In vivo inhibition of miR-7a in Pax6-negative regions of the lateral wall induced Pax6 protein expression and increased dopaminergic neurons in the olfactory bulb. These findings establish miRNA-mediated fine-tuning of protein expression as a mechanism for controlling neuronal stem cell diversity and, consequently, neuronal phenotype.

Adding a spatial dimension to postnatal ventricular-subventricular zone neurogenesis

“…Viral transduction through this basal process targets NSCs in smaller V-SVZ areas, allowing investigators to describe postnatal V-SVZ regionalization in exquisite detail (Merkle et al, 2007(Merkle et al, , 2014. Results obtained by viral infection, genetic fatemapping or targeted electroporation experiments revealed that CR + PGCs are preferentially generated in the medial V-SVZ (Merkle et al, 2007(Merkle et al, , 2014Fernandez et al, 2011), whereas superficial GCs, tyrosine hydroxylase (TH)-expressing PGCs and a small number of glutamatergic juxtaglomerular cells are preferentially generated in the dorsal V-SVZ (Merkle et al, 2007;Young et al, 2007;Brill et al, 2009;Fernandez et al, 2011;de Chevigny et al, 2012), and deep GCs as well as CB + [expressing calbindin; also known as calbindin 1 (Calb1)] PGCs in the lateral aspect of the V-SVZ (Merkle et al, 2007;Young et al, 2007;Fernandez et al, 2011). A closer analysis of NSCs located in the most anterior ventral regions of the LV revealed the existence of additional microdomains.…”

“…The V-SVZ itself is therefore regionalized along the anteroposterior axis: rostrally located NSCs give rise to GCs that are more superficial in the GC layer than those generated by more caudally located NSCs (Kelsch et al, 2007). Furthermore, the V-SVZ is also patterned along the dorsoventral axis: selective electroporation of postnatal V-SVZ subregions (Fernandez et al, 2011;de Chevigny et al, 2012) showed that NSCs from the medial wall are biased to generate PGCs (>85%), whereas those from the lateral wall primarily adopt a GC fate (>90%). In an intermediate fashion, NSCs located in the dorsal wall generate PGCs and GCs in a 1 to 2 proportion (Fernandez et al, 2011).…”

Neonatal Subventricular Zone Electroporation

“…However, electroporation can be tailored to the requirement of the respective experiment but not sweeping the electrode and using specific placement and orientation as detailed in the video. For example, since dorsally localized radial glia differ from those lining the lateral section of the ventricle, one can chose to only electroporate a single region 9,10 . Further specificity can also be given using smaller electrodes.…”

“…Close attention should be given to the placement given the heterogeneity of stem cell populations along the SVZ 8 . Differences in the rates of proliferation and cell fate have been identified for ventral-dorsal and rostral-caudal locations 9,10 .…”

Un microARN régule la production de neurones dopaminergiques dans le cerveau antérieur

“…Nous avons montré qu'un microARN, miR-7a, limite la genèse de neurones dopaminergiques dans le bulbe olfactif post-natal en inhibant l'expression de la protéine Pax6 dans les précurseurs neuronaux des parois ventriculaires laté-rales [10]. Ce résultat nouveau ajoute un niveau de complexité à la régulation moléculaire de la destinée neuronale dans le cerveau adulte.…”