Pax6 Expression Is Sufficient to Induce a Neurogenic Fate in Glial Progenitors of the Neonatal Subventricular Zone

Eun Sook Jang,James E Goldman

doi:10.1371/journal.pone.0020894

Abstract

BackgroundThe forebrain subventricular zone (SVZ) of neonatal mammals contains a large, heterogeneous population of migratory and proliferating precursors of interneurons and glia. These cell types are produced in large numbers in the immediate postnatal period, the glioblasts populating the hemispheres with astrocytes and oligodendrocytes, the neuroblasts migrating to the olfactory bulb to become interneurons. How cell fate decisions are determined or stabilized in this mixed population is not clear, although previous studies indicate the importance of two transcription factors, Pax6 in neurons and Olig2 in glia, and suggest there may be reciprocal repression between these genes.Methodology/Principal FindingsIn examining the SVZ of neonatal mouse and rat brain, we find that the very large majority of SVZ cells express either Pax6 or Olig2, but few express both. We have used in vivo retro- and lenti-virus injections into the neonatal SVZ and in vitro gene transfer to demonstrate that pax6 over-expression is sufficient to down-regulate olig2 and to promote a neuronal lineage development and migration pattern in olig2-expressing cells. Furthermore, we provide evidence that Pax6 binds to the olig2 promoter and that an HEB sequence in the promoter is required for the Pax6 repression of olig2 transcription. Lastly, we constructed a lentivirus to target olig2-expressing cells in the SVZ to trace their fates, and found that the very large majority developed into glia.Conclusions/SignificanceWe provide evidence for a direct repression of olig2 by Pax6. Since SVZ cells can display developmental plasticity in vitro, the cross-repression promotes a stabilization of cell fates. This repression may be critical in a germinal zone in which immature cells are highly migratory and are not organized into an epithelium.

Highlights

During the first few postnatal weeks of rodent forebrain development, the subventricular zone (SVZ) generates both neurons and glia [1,2,3,4,5].OHHO This is a region of highly migratory and proliferative cells, glioblasts populating the hemispheres with astrocytes and oligodendrocytes, and neuroblasts migrating to the olfactory bulb, where they become interneurons
Olig2+ cells were found in the SVZ, where they tended to concentrate in the center and periphery of the region, and in tissue surrounding the RMS, but few appeared in the RMS itself (Fig. 1a, b) [20]
We found that a consensus Pax6 site and an HEB site on the olig2 promoter are separated by only about a dozen base pairs

Summary

Introduction

During the first few postnatal weeks of rodent forebrain development, the subventricular zone (SVZ) generates both neurons and glia [1,2,3,4,5].OHHO This is a region of highly migratory and proliferative cells, glioblasts populating the hemispheres with astrocytes and oligodendrocytes, and neuroblasts migrating to the olfactory bulb, where they become interneurons. The forebrain subventricular zone (SVZ) of neonatal mammals contains a large, heterogeneous population of migratory and proliferating precursors of interneurons and glia These cell types are produced in large numbers in the immediate postnatal period, the glioblasts populating the hemispheres with astrocytes and oligodendrocytes, the neuroblasts migrating to the olfactory bulb to become interneurons. How cell fate decisions are determined or stabilized in this mixed population is not clear, previous studies indicate the importance of two transcription factors, Pax in neurons and Olig in glia, and suggest there may be reciprocal repression between these genes

Methods

Results

Conclusion