A20: Generation of transgenic mice for the inducible expansion of neural stem cells
Project leader: Dr. F. Calegari
Essentially all neurons, astrocytes and oligodendrocytes of the mammalian brain are generated during embryonic and early postnatal development by divisions of neural stem and progenitor cells (Götz and Huttner, 2005).
In the context of cell cycle progression of neural stem cells, it has been observed that their G1 increases as they switch from proliferation to neurogenesis (Calegari et al., 2005) and that an artificial lengthening of G1 alone is sufficient to induce premature neurogenesis (Calegari and Huttner, 2003). Conversely, we recently found that shortening the G1 of neural progenitors of the developing mouse brain is sufficient to inhibit neurogenesis and increase the expansion of progenitors that ultimately contribute to a three-fold wider cortical surface area of the postnatal brain (Lange et al., in press).
Therefore, G1 lengthening is both necessary and sufficient to induce the switch of neural stem cells from proliferation to neurogenesis and manipulation of G1 can be used to expand neural stem cells and, perhaps, increase brain size.
We now plan to fully exploit these observations and develop systems that allow the study of neural stem cell contribution to tissue formation during brain development.
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Götz M, and Huttner WB (2005). The cell biology of neurogenesis. Nat Rev Mol Cell Biol 6:777-88.
Calegari F, Haubensak W, Haffner C and Huttner WB (2005) Selective lengthening of the cell cycle in the neurogenic subpopulation of neural progenitor cells during mouse brain development. J Neurosci 25:6533-8.
Calegari F and Huttner WB (2003) An inhibition of cyclin-dependent kinases that lengthens, but does not arrest, neuroepithelial cell cycle induces premature neurogenesis. J Cell Sci 116:4947-55.
Lange C Huttner WB and Calegari F. Cdk4/cyclinD1 overexpression in mouse neural progenitors shortens G1, delays neurogenesis and promotes the expansion of basal (intermediate) progenitors. Cell Stem Cell, in press.
