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UCL Great Ormond Street Institute of Child Health

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Paula Alexandre's research group

Stem Cell Renewal & Neurogenesis

During normal brain development brain cells have to self-renew while producing neurons. Understanding the cellular and molecular mechanisms underlying brain cells behavior, proliferation and differentiation will be a major advance in our understanding of vertebrate brain development, regeneration, and diseases such as brain cancer and neurological conditions in humans.

Our lab is now currently investigating the different molecular mechanisms that may regulate self-renewal and differentiation in stem cell niches and developing brain.
We use state-of-art live-imaging in zebrafish and mammalian systems to follow individual cell behaviours in their native environment (see examples: movie1 and 2).

Asymmetric division and new mechanisms of self-renewal

Figure 1

During normal brain development there is a tightly controlled balance between brain growth and production of neurons. One of the processes that allows this mode of development is called asymmetric cell division and involves the generation of two distinct daughter cells (see figure 1 for example: a neuron and a progenitor) from a single cell division. Little was known about the regulation of asymmetric mode of division in vertebrates brain. By using live-imaging approach in zebrafish, we demonstrated for the first time that asymmetric inheritance of apical domain correlates with asymmetric divisions.

The inheritance of apical domain was for a long time thought to be important for establishing and maintaining epithelial structure and was therefore predicted to be important for progenitor cell identity. However, this is not the case in zebrafish and other vertebrates systems in which inheritance of the apical Par3 domain is in fact correlated with neuronal cell fates (see Figure 2) (Alexandre et al, 2010).

Figure 2 rev

The daughter cells that lose contact with the apical surface during cell division are able to re-attach apically. We are now testing whether the regain of apical attachment could be a new mechanism of self-renewal, essential for maintaining the progenitor and stem cell populations.We also observed that basal process can be symmetrically and asymmetrically inherited during cell division (movie 1 and 2) ( Kosodo et al, 2008) and that progenitor daughter inherits the basal process during asymmetric divisions (Alexandre et al, 2010).

These new findings were only made possible by using this cutting-edge live–imaging approach in zebrafish embryos, which we showed to offer unrivalled advantages in terms of optics and for analysis of dynamic subcellular events at an individual cell level.