Abstract
Whether induction of low-level neurogenesis in normally non-neurogenic regions of the adult brain mimics aspects of developmental neurogenesis is currently unknown. Previously, we and others identified that biophysically induced, neuron subtype-specific apoptosis in mouse neocortex results in induction of neurogenesis of limited numbers of subtype-appropriate projection neurons with axonal projections to either thalamus or spinal cord, depending on the neuron subtype activated to undergo targeted apoptosis. Here, we test the hypothesis that developmental genes from embryonic corticogenesis are re-activated, and that some of these genes might underlie induction of low-level adult neocortical neurogenesis. We directly investigated this hypothesis via microarray analysis of microdissected regions of young adult mouse neocortex undergoing biophysically activated targeted apoptosis of neocortical callosal projection neurons. We compared the microarray results identifying differentially expressed genes with public databases of embryonic developmental genes. We find that, following activation of subtype-specific neuronal apoptosis, three distinct sets of normal developmental genes are selectively re-expressed in neocortical regions of induced neurogenesis in young adult mice: (1) genes expressed by subsets of progenitors and immature neurons in the developing ventricular and/or subventricular zones; (2) genes normally expressed by developmental radial glial progenitors; and (3) genes involved in synaptogenesis. Together with previous results, the data indicate that at least some developmental molecular controls over embryonic neurogenesis can be re-activated in the setting of induction of neurogenesis in the young adult neocortex, and suggest that some of these activate and initiate adult neuronal differentiation from endogenous progenitor populations. Understanding molecular mechanisms contributing to induced adult neurogenesis might enable directed CNS repair.
Highlights
IntroductionThere is increasing evidence that elements of the molecular controls over developmental neurogenesis during brain formation control homologous aspects of constitutive neurogenesis in the hippocampal dentate gyrus and olfactory bulb (Magavi et al, 2005; Sohur et al, 2006; Steele et al, 2006; Alvarez-Buylla et al, 2008; Suh et al, 2009; Ma et al, 2010; Kempermann, 2011), but whether the same is true of induction of neurogenesis in normally non-neurogenic regions is unknown
We find that, following activation of subtype-specific neuronal apoptosis, three distinct sets of normal developmental genes are selectively re-expressed in neocortical regions of induced neurogenesis in young adult mice: (1) genes expressed by subsets of progenitors and immature neurons in the developing ventricular and/or subventricular zones; (2) genes normally expressed by developmental radial glial progenitors; and (3) genes involved in synaptogenesis
We find that regions of young adult neocortex undergoing induction of neurogenesis differentially express genes that are active during normal development in neural precursors and radial glia, and during synaptogenesis
Summary
There is increasing evidence that elements of the molecular controls over developmental neurogenesis during brain formation control homologous aspects of constitutive neurogenesis in the hippocampal dentate gyrus and olfactory bulb (Magavi et al, 2005; Sohur et al, 2006; Steele et al, 2006; Alvarez-Buylla et al, 2008; Suh et al, 2009; Ma et al, 2010; Kempermann, 2011), but whether the same is true of induction of neurogenesis in normally non-neurogenic regions is unknown. It is increasingly being identified that there is remarkable heterogeneity and diversity of partially fate-restricted progenitors in the developing CNS (Chambers et al, 2001; Hack et al, 2005; Kohwi et al, 2005; Molyneaux et al, 2005; Wu et al, 2005; Gal et al, 2006; Costa et al, 2007; Merkle et al, 2007; Mizutani et al, 2007; Lai et al, 2008; Lledo et al, 2008; Azim et al., 2009a) and that there are lineage- and subtype-specific molecular controls over the specification, differentiation, and ultimate function of broad classes and distinct subtypes of cortical projection neurons (Arlotta et al, 2005; Chen et al, 2005; Molyneaux et al, 2005, 2007; Ozdinler and Macklis, 2006; Sohur et al, 2006; Alcamo et al, 2008; Britanova et al, 2008; Joshi et al, 2008; Lai et al, 2008; Azim et al, 2009a,b; Bedogni et al, 2010; Tomassy et al, 2010; Han et al, 2011; McKenna et al, 2011) These studies are beginning to identify the complex molecular controls over developmental neurogenesis within the mammalian neocortex. Based on the similarities and conserved mechanisms identified by many groups between developmental and adult neurogenesis in the hippocampal dentate gyrus and olfactory bulb, we hypothesized that there might potentially www.frontiersin.org
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