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Figuring out the ups and downs--and sideways--of neural development

Cell Press

One of the key controllers of neural development seems to depend on a simple cellular decision--whether to divide perpendicularly or in parallel to the embryonic structure called the neuroepithelium. Nevertheless, such orientation is critical, and understanding its machinery could help neuroscientists learn to control the division of adult neural stem cells to regenerate neural tissues.

Researchers know that during the earliest embryonic brain development, neural stem cells divide "symmetrically," producing identical immature progenitor cells that continue to proliferate. A bit later, however, when neural tissues need to begin to differentiate, the cells divide "asymmetrically," producing one proliferating progenitor and another that stops proliferating and differentiates into an adult neural cell. And during final brain development, the cells return to symmetric cell division, creating differentiated adult cells.

The two types of cell division seem to be governed by the orientation of the tiny bundles of fiber-like microtubules called spindles inside the dividing cell--whether the spindles are oriented parallel or perpendicular to the neuroepithelium. These spindles attach to the dividing chromosomes in the nucleus and drag the two copies apart, ensuring that each daughter cell has its fair share.

In an article in the November 23, 2005, issue of Neuron, Mihaela Žigman and colleagues have pinpointed a key regulator of spindle orientation in mammals. They drew on discoveries made in the fruit fly Drosophila, in which other researchers had found a gene called Inscuteable to be a central controller of spindle orientation. Analyzing genetic databases, Žigman and colleagues determined that versions of the Inscuteable gene could be found in higher animals, including mice, rats, and humans. Also, they found in their experiments, the mammalian version of Inscuteable (mInsc) appeared in regions of the cell and activated itself at times during cell division that was consistent with a role in spindle orientation.

Studying developing retinal tissue of embryonic rats, they observed that the protein produced by the mInsc gene concentrated at places in the developing cell that suggested a role in controlling spindle orientation.

And in key experiments, when they knocked-out activity of mInsc in the rat retina, they found abnormal spindle orientation. And importantly, in the rats lacking mInsc activity, they also observed abnormal retinal development, apparently because of a continued division that favors proliferating progenitor cells. In that tissue, the number of normal photoreceptor cells was reduced and the number of another type of neuron increased.

"We show that mInsc depletion ablates vertical mitotic spindle orientation in retinal progenitors and leads to defects in cell-fate specification and proliferation," concluded Žigman and colleagues. "Our results demonstrate that spindle orientation not only predicts but actually determines the fate of the two daughter cells.

"This identification of mInsc provides a unique tool to analyze the importance of oriented divisions in various other vertebrate tissues," they wrote. "For example, it was proposed that adult mammalian neural stem cells divide asymmetrically along the apical basal axis. It will be interesting to test whether spindle orientation is essential for asymmetric stem cell divisions as well. If so, this will be an important factor in exploring the regenerative capacity of these cells."

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The researchers include Mihaela Žigman and Juergen A. Knoblich of the Austrian Academy of Sciences (IMBA) in Vienna, Austria; Michel Cayouette of the Institut de recherches cliniques de Montreal (IRCM) in Montreal, Quebec and Stanford University School of Medicine in Stanford, CA; Christoforos Charalambous of the Research Institute of Molecular Pathology (I.M.P.) and the Medical University of Vienna in Vienna, Austria; Alexander Schleiffer, Dara Dunican and Nicole Firnberg of the Research Institute of Molecular Pathology (I.M.P.) in Vienna, Austria; Oliver Hoeller of the Research Institute of Molecular Pathology (I.M.P.) in Vienna, Austria and the Medical Research Council (MRC) in Cambridge, United Kingdom; Christopher R. McCudden and David P. Siderovski of the University of North Carolina in Chapel Hill, NC; Ben A. Barres of Stanford University School of Medicine in Stanford, CA. This research was supported by Work in J.A.K.'s lab is supported by the Austrian Academy of Sciences and the Austrian Research Fund (FWF). Work in M.C.'s lab is funded by the Canadian Institute of Health Research. Work in D.P.S.'s lab is funded by NIH grants R01 GM062338 and P01 GM065533. Work in B.A.B.'s lab is funded by NIH grant NEI R01 EY11310.

Žigman et al.: "Mammalian Inscuteable regulates spindle orientation and cell fate in the developing retina." Publishing in Neuron, Vol. 48, 539-545, November 23, 2005, DOI 10.1016/j.neuron.2005.09.030, www.neuron.org

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