Project

Discipline

Brain; Subventricular zone; Neurogenesis; Hippocampus; Neural stem cells

Lead
Lay summary
The brain is generated by the regulated production of neurons and glial cell from pools of neural stem cells. Defects in neural stem cell function may be responsible for some congenital brain malformations, neurological abnormalities and psychological disorders in humans. Importantly, stem cells remain in some regions of the adult mammalian brain but fail to regenerate new brain tissue after injury or during disease. We aim to understand the molecular mechanisms that control the regulation of neural stem cells and how these signals may be influenced by disease and aging. Over the past few years, we have identified a striking diversity in the neural stem cell pools within the adult mammalian brain. Using genetic analyses we are now able to identify, trace and isolate these different neural stem cell populations and to study their transition between active and quiescent states. Recently, we have identified a novel mechanism of neural stem cell regulation whereby the expression of key regulatory proteins is directly controlled by mRNA destabilization in addition to gene expression. We plan experiments to study in more detail the molecular machinery that controls the process of neural stem cell differentiation beyond the level of the gene. We will identify other targets of this molecular pathway through state-of-the-art molecular genetics. In addition, we will study the signaling mechanisms that control differences in stem cell activity during aging and disease. A deeper understanding of the regulatory mechanisms that control the activity of neural stem cells in the developing and adult brain and their differentiation potential could have wide reaching implications for human therapy and potentially brain regeneration.

Direct link to Lay Summary

Last update: 21.02.2013

Active participation

Self-organised

Number	Title	Start	Funding scheme

The regulation of neural stem cell (NSC) maintenance and differentiation is crucial for formation of the central nervous system (CNS). A detailed understanding of NSC biology has important implications for comprehending congenital brain malformations, age-related disorders, neurological diseases and regeneration. Established genetic tools, in vivo and in vitro experimental approaches for manipulation and lineage tracing, make neural progenitors an attractive experimental paradigm. The patterned and structured formation of the mammalian brain and positional fate restriction assists in the analysis of phenotypes and gene functions. Further, congenital brain malformations can often be traced to aberrant proliferation, differentiation or specification of neural progenitors. The production of new neurons also plays important roles in the adult mammalian brain. In rodents, neurons of the olfactory system are continually regenerated from the subventricular zone (SVZ), rebuilding complex multi-neuron circuits. New neurons in the hippocampal dentate gyrus (DG) are important for specific forms of memory and learning in mice. Although the role of neurogenesis in the human brain is debated, links to pathologies including epilepsy, depression and brain tumors underline the importance of understanding the mechanism controlling NSCs. The potential of NSC for regeneration and rejuvenation also emphasize a need to fill the gaps in our basic knowledge of NSC biology.My lab has focused on the role of Notch signaling in NSC maintenance1-4. By generating and combining transgenic mice with analysis of homeostasis, physical activity, degeneration, regeneration aging and in vitro approaches, we determined that NSCs are a heterogeneous cell population even within the same niche1,2,4-6. Recently, we found that the adult SVZ and DG contain active and dormant NSCs1,5-7. Active NSCs express brain lipid binding protein (BLBP), drive neurogenesis, and there loss is one potential cause of the age-dependent decline in neurogenesis. BLBP+ active NSCs have not been studied in detail, either during homeostasis, aging nor regeneration. We have generated tools including transgenic mice to study these active and dormant NSCs in greater detail. We will use these tools to continue to deepen our knowledge of NSCs in the brain. We will lineage trace different NSC populations in vivo, addressing dormant, quiescent and active NSCs and elucidating their roles in homeostasis and regeneration. We will study the effects that pathophysiological stimuli have on these NSC populations. Recently we found that active NSCs depend upon Notch1 but dormant NSCs do not. Dormant NSCs express Notch2 and Notch3, hence, we will assess the functions of Notch1, Notch2 and Notch3 in the different NSCs populations of the brain. The control of NSC activity and dormancy has clinical relevance for regeneration but also for rejuvenation to combat age-related disorders. We have generated transcription profiles of embryonic and adult Hes5::GFP+ NSCs and of Notch1-regulated genes in NSCs. Many components of the microRNA (miRNA) biogenesis pathway were present in these profiles. Therefore, we targeted the root of miRNA biogenesis, conditionally ablating key components of the miRNA microprocessor (MP) in forebrain NSCs. We established that the MP and Drosha, unlike Dicer, play a central role in regulating NSCs during development. An important function of the MP in NSCs is a novel miRNA-independent mechanism to directly target stem-loop hairpin structures in the Ngn2 mRNA. We will extend our previous findings of MP function in neurogenesis, identify novel targets of the MP and extend the analysis of MP function to active and dormant NSCs during aging and regeneration.