Abstract
Radial Glia (RG) cells constitute the major population of neural progenitors of the mouse developing brain. These cells are located in the ventricular zone (VZ) of the cerebral cortex and during neurogenesis they support the generation of cortical neurons. Later on, during brain maturation, RG cells give raise to glial cells and supply the adult mouse brain of Neural Stem Cells (NSC). Here we used a novel transgenic mouse line expressing the CreERT2 under the control of AspM promoter to monitor the progeny of an early cohort of RG cells during neurogenesis and in the post natal brain. Long term fate mapping experiments demonstrated that AspM-expressing RG cells are multi-potent, as they can generate neurons, astrocytes and oligodendrocytes of the adult mouse brain. Furthermore, AspM descendants give also rise to proliferating progenitors in germinal niches of both developing and post natal brains. In the latter –i.e. the Sub Ventricular Zone- AspM descendants acquired several feature of neural stem cells, including the capability to generate neurospheres in vitro. We also performed the selective killing of these early progenitors by using a Nestin-GFPflox-TK allele. The forebrain specific loss of early AspM expressing cells caused the elimination of most of the proliferating cells of brain, a severe derangement of the ventricular zone architecture, and the impairment of the cortical lamination. We further demonstrated that AspM is expressed by proliferating cells of the adult mouse SVZ that can generate neuroblasts fated to become olfactory bulb neurons.
Highlights
Radial Glia cells (RGs) derive from neuroepithelial cells of the early embryos
AspM-CreERT2 transgene targets Cre-mediated recombination in long term proliferating cells of the cerebral cortex In order to trace the progeny of early AspM expressing cells, we generated a transgenic mouse line, in which the inducible Cre recombinase (CreERT2) [23,24,25] -i.e. transiently activated by injecting mice with Tamoxifen (Tam) [26,27], was placed under the control of AspM cis-acting regions (Figure S1A and [material method] section for a detailed description of the construct)
RT-PCR experiments on microdissections of peri-ventricular regions of the lateral ventricle confirmed that both AspM and Cre mRNAs are expressed in the postnatal sub ventricular zone (SVZ) (Figure S1F)
Summary
Radial Glia cells (RGs) derive from neuroepithelial cells of the early embryos. At the onset of neurogenesis, RG cells perform symmetric and asymmetric division to support either the proliferating pool of cells or the generation of cortical plate neurons. RG cells are fated to become glial cells in the post natal brain and a subset of them is maintained and propagated in specialized germinal/neurogenic niches of the adult brain, as neural stem cells (NSCs) [1]. NSCs are located in the sub ventricular zone (SVZ) of the lateral ventricle and in the dentate gyrus of the hippocampus [2,3]. SVZ-restricted NSCs cells generate fast cycling precursors –i.e. type-C progenitors- that subsequently give raise to neural precursor cells (type-A, neuroblasts), fated to become olfactory bulb neurons [2]. NSCs, are multipotent cells, because in vitro [4] and in vivo they can generate, neurons, oligodendrocytes and astrocytes of the adult brain [5,6,7,8]
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