Asymmetric division of neural stem / progenitor cells

    In Drosophila neuroblasts, cell fates are regulated by asymmetric distribution of molecular determinants and the direction of the mitotic spindle. In vertebrate embryos and mammalian cells the significance of asymmetric division and spindle orientation for cell type specification is less well studied. We would like to understand the role for mitotic spindle orientation and asymmetric cell division of neural progenitor cells (NPCs) in neuronal cell fate determination.

    Our studies demonstrate that Lgl is required for cell polarity and asymmetric cell division during primary neurogenesis in Xenopus ectoderm (Fig. 1), and its localization may be controlled by Wnt signaling (Dollar et al., 2005, and not shown). As neural stem cells may undergo similar asymmetric divisions, we hypothesize that the role of Lgl as an essential regulator of neuronal differentiation is preserved in these cells (Fig. 2).

    Since the Wnt signaling pathway is known to be involved in the regulation of cell polarity and mitotic spindle orientation in C. elegans embryos, we use transgenic mice and frog

embryos to investigate a role for Wnt signaling in asymmetric cell divisions during vertebrate neurogenesis.

Figure 1. Primary neurons marked by N-tub in a frog embrio

     Both Lgl and the Par proteins are highly conserved from worms to humans and function to regulate cell polarity in many embryonic tissues. Lgl has been shown to control asymmetric cell division and differentiation of Drosophila neuroblasts and mouse neural tube. We are studying the subcellular localization of Lgl and Par proteins in cells undergoing neural differentiation and assess how modulation of their levels or localization would influence neural tissue differentiation. The knowledge of molecular mechanisms regulating neuronal differentiation should have implications on stem cell research and regenerative medicine.

Figure 2. Cell fates are regulated by asymmetric distribution of molecular determinants and the direction of the mitotic spindle. Possible inheritance of cell fates in two daughters of a progenitor undergoing symmetric (left) vs asymmetric (right) division is shown.

© 2008 Mount Sinai Medical Center