The mammalian brain has a remarkable capacity for plasticity, critical for learning and memory and compensating for damage. However, the brains of mammals regenerate poorly, failing to generate appreciable numbers of new neurons. This was thought to be due to a lack of stem and progenitors cells in the postnatal brain, including in humans. It is accepted that the adult brain contains neural stem cells (NSCs) and in some species continue to generate neurons. Newborn adult neurons in the lateral forebrain and in the hippocampus contribute to olfaction and specific forms of memory, respectively. Using conditional mouse genetics and cell culture we are trying to understand the molecular mechanisms controlling NSC activity and fate during development and adulthood. We are also trying to elucidate why active NSCs are lost in infant humans and during aging.
We and others have demonstrated the importance of Notch signaling in regulating NSC maintenance and cell fate during development. Notch controls the Expression of a cascade of transcription factors critical for progenitor maintenance and differentiation. Although transcriptional regulation of target genes is pivotal, we have addressed other mechanisms controlled by Notch signaling and which contribute to neurogenesis. We performed ge- nome-wide studies of NSC transcriptomes following ablation of Notch. We study a cluster of RNA-binding proteins and components of the microRNA pathway that are regulated downstream of Notch in NSCs. We showed that the RNAseIII Drosha and DGCR8/Pasha, key components of the microRNA microprocessor, play a central role in neurogenesis in the embryonic mouse forebrain. Drosha negatively regulates Expression of the proneurogenic transcription factors Neurogenin2 and NeuroD1 through binding to and cleaving hairpin structures in their mRNAs to destabilize the transcripts. We continue to study the role on mRNA destabilization to expand our understanding of the targets of the Drosha/DGCR8 complex in NSCs of the mammalian brain.
NSCs in the adult forebrain are confined to niches in the subventricular zone (SVZ) and hippocampus (Fig.1). Most NSCs are quiescent, proliferate sporadically, and produce committed neurogenic progeny. The SVZ and hippocampus retain a remarkable capacity for repair indicating the importance of NSCs in the regeneration process. We uncovered a difference in Notch dependence between active neurogenic and dormant regenerative NSCs. Loss of Notch1, one member of the four-strong Notch family, results in a selective loss of activated neurogenic NSCs. In contrast, dormant NSCs are Notch1-insensitive until stimulated by a lesion to the SVZ. Hence, Notch1 is a key component of the adult SVZ niche promoting maintenance of neurogenic and activated NSC (Fig. 2). Using genetic markers and lineage tracing we addressed NSC heterogeneity in the adult brain. We identified subpopulations of adult SVZ NSCs (type 1-3) and found that activated NSCs express brain lipid binding protein (BLBP, FABP7) and epidermal growth factor (EGF) receptor (Fig. 1A). They proliferate in response to EGF and are a major clonogenic population in the SVZ. We found a similar population of BLBP-expressing mitotic progenitors in the postnatal human brain and these activated NSCs are diminished in aged rodents and humans leaving only dormant stem cells.
We also identified morphologically distinct NSCs in the hippocampus of adult mice that can shuttle between mitotic activity and quiescence (Fig. 2B). Radial and horizontal NSCs respond selectively to neurogenic and pathophysiological stimuli including physical exercise and epileptic seizures. We found that the age-related reduction in neurogenesis in the hippo- campus correlates with a loss of active horizontal NSCs and their transition to a quiescent state rather than a loss of all stem cells. These geriatric quiescent NSCs can be reactivated to rejuvenate hippocampal neurogenesis in aged mice. The selective response of NSC populations and reversible quiescence has important implications for adaptive learning and for regenerative therapy.

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Our research areas include

  • Genetic analysis of neurogenesis in the developing and adult mouse brain
  • Notch signaling and its control of neurogenesis
  • Diversity in the adult forebrain NSC population
  • The role of Drosha in regulating neurogenesis
  • Glioblastomas in the adult brain

Latest Publication

Giachino, C. et al., Development

Adult neurogenesis is tightly regulated through the interaction of neural stem/progenitor cells (NSCs) with their niche. Neurotransmitters, including GABA activation of GABAA receptor ion channels, are important niche signals. We show that adult mouse hippocampal NSCs and their progeny express metabotropic GABAB receptors. Our data indicate that signaling through GABAB receptors is an inhibitor of adult neurogenesis.

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