Key factor in brain development revealed, offers insight into disorder

Scientists have had evidence that, in addition to their role in migration in immature nerve cells, the human and mouse forms of the gene may play a role in cell division and proliferation processes in radial glial progenitor cells. However, scientists have not known what that role would be. Nor have they known what role, if any, the gene plays earlier on in brain development -- in neuroepithelial stem cells, themselves.

In their study, reported in the Feb. 8 issue of Cell, the scientists investigated embryonic mice genetically engineered to completely lack Lis1 in their cells at various stages of embryonic development. In a surprising finding, they discovered that Lis1 is essential for cell division in neuroepithelial stem cells. It also is important, though not essential, for cell division in the radial glial progenitor cells.

Lis 1, they showed, plays a critical role in ensuring that neuroepithelial stem cells divide symmetrically, so that both daughter cells receive the full set of duplicated chromosomes and the molecular components that support cell functions. It does so by helping regulate the orientation of the cells’ mitotic spindles -- the microtubules that draw the two sets of chromosomes into position on either side of the dividing mother cell and that demarcate, at their center, the cleavage point of cell division.

Specifically, Lis 1 makes sure that the mitotic spindle is oriented perpendicular to the top and base components of the neuroepithelial stem cells, so that each daughter cell not only receives the appropriate genetic material but also contains molecular components at the top and bottom, or the basal and apical, portion of the cell membrane, respectively.

“In neuroepithelial stem cells, the apical and basal plasma membranes are only a tiny fraction of the total cell membrane, so the orientation of division must be precisely controlled either to make sure that both sides of each of the daughter cells are attached at both the apical and basal surfaces as they rapidly divide or to distribute apical and basal components equally to the daughter cells,” says Wynshaw-Boris.

The scientists hypothesize that Lis1 carries out the role by directing the movement of a molecular motor known as dynein to the surface of both sides of the cell membrane. There, dynein takes a fixed position and, like a molecular hook, pulls the microtubules that emanate from the middle of the cell toward it.