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PMID:16798874

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Citation

Fish, JL, Kosodo, Y, Enard, W, Pääbo, S and Huttner, WB (2006) Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells. Proc. Natl. Acad. Sci. U.S.A. 103:10438-43

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.

Links

PubMed PMC1502476 Online version:10.1073/pnas.0604066103

Keywords

Animals; COS Cells; Cell Proliferation; Cercopithecus aethiops; Down-Regulation; Female; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitotic Spindle Apparatus/metabolism; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Neuroepithelial Cells/cytology; Neuroepithelial Cells/metabolism; RNA Interference

Significance

Annotations

Gene product Qualifier GO ID GO term name Evidence Code with/from Aspect Notes Status


See also

References

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