Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells

doi:10.1073/pnas.0604066103

Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells

*Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, D-01307 Dresden, Germany; and
^§Max Planck Institute of Evolutionary Anthropology, Deutscher Platz 6, D-04103 Leipzig, Germany

Communicated by Kai Simons, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany, May 17, 2006
↵ ^†J.L.F. and Y.K. contributed equally to this work. (received for review March 24, 2006)

Abstract

The ASPM (abnormal spindle-like microcephaly-associated) protein has previously been implicated in the determination of human cerebral cortical size, but the cell biological basis of this regulation has not been studied. Here we investigate the role of Aspm in mouse embryonic neuroepithelial (NE) cells, the primary stem and progenitor cells of the mammalian brain. Aspm was found to be concentrated at mitotic spindle poles of NE cells and to be down-regulated with their switch from proliferative to neurogenic divisions. Upon RNA interference in telencephalic NE cells, Aspm mRNA is reduced, mitotic spindle poles lack Aspm protein, and the cleavage plane of NE cells is less frequently oriented perpendicular to the ventricular surface of the neuroepithelium. The alteration in the cleavage plane orientation of NE cells increases the probability that these highly polarized cells undergo asymmetric division, i.e., that apical plasma membrane is inherited by only one of the daughter cells. Concomitant with the resulting increase in abventricular cells in the ventricular zone, a larger proportion of NE cell progeny is found in the neuronal layer, implying a reduction in the number of NE progenitor cells upon Aspm knock-down relative to control. Our results demonstrate that Aspm is crucial for maintaining a cleavage plane orientation that allows symmetric, proliferative divisions of NE cells during brain development. These data provide a cell biological explanation of the primary microcephaly observed in humans with mutations in ASPM, which also has implications for the evolution of mammalian brains.

Footnotes

^¶To whom correspondence should be addressed. E-mail: huttner{at}mpi-cbg.de
↵ ^‡Present address: Center for Developmental Biology, RIKEN, Kobe 650-004, Japan.
Author contributions: J.L.F., Y.K., W.E., S.P., and W.B.H. designed research; J.L.F. and Y.K. performed research; J.L.F., Y.K., and W.B.H. analyzed data; and J.L.F. and W.B.H. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

Abbreviations:

NE,

neuroepithelial;

VZ,

ventricular zone;

RNAi,

RNA interference;

esiRNA,

endoribonuclease-prepared, short interfering RNA;

En,

embryonic day n.