Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells

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 downregulated 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.asymmetric division ͉ brain size evolution ͉ cleavage plane ͉ neurogenesis

Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target

“…ASPM also has been recognized as a critical regulator of brain size, likely via its role in promoting neuroblast proliferation and symmetric division (28)(29)(30)45). Our data showing that neural stem cell differentiation results in loss of ASPM expression and that siRNAmediated knockdown of ASPM specifically inhibits neural stem cell self renewal and glioblastoma growth suggests the possibility that this gene may be involved in glioblastoma pathogenesis by promoting a stem cell phenotype.…”

The microenvironment of the embryonic neural stem cell: Lessons from adult niches?

“…This is an interesting observation, as the centrosome is a key organelle in determining the angle of cell division by orientation of the mitotic spindle (Hyman and White, 1987;Hyman, 1989;Grill et al, 2001). In the case of ASPM, a direct role in the regulation of division angle and the subsequent plane of cell cleavage has been shown in neural stem cells within the VZ (Fish et al, 2006). Alterations in the angle of division would be predicted to have a major effect on the balance between symmetrical and asymmetrical divisions.…”

“…A similar phenotype could be caused by abnormalities of mitotic spindle orientation that would perturb the distribution of fate determinants and so alter cell fate (e.g., by premature neurogenesis) following division. Such a mechanism provides a hypothetical explanation for the human microcephaly syndromes that result from mutations in genes encoding centrosomal proteins (Bond and Woods, 2006), one of which (ASPM) has been shown to regulate cleavage plane angle and neurogenesis directly (Fish et al, 2006). Loss of apical adhesion could result in displacement of the NSC into deeper cortical layers, generating a random distribution of cells (NSCs, basal progenitors, and differentiated cells) in the cortex and a possible increase in the number of intermediate progenitors and differentiated cells as seen in Rho-GTPase cdc42 mutants (Cappello et al, 2006) and aPKC (Imai et al, 2006).…”

The Centrosome and Its Duplication Cycle

“…In cultured human cells, ASPM localizes to centrosomes and spindle poles, similar to its fly and worm ortholog (Saunders et al 1997;Kouprina et al 2005;van der Voet et al 2009;Noatynska et al 2012). Neuroprogenitors depleted of ASPM fail to orient the mitotic spindle perpendicular to the ventricular surface of the neuroepithelium giving asymmetric, rather than symmetric, divisions (Fish et al 2006). Mutations in CPAP (MCPH6) and STIL (MCPH7) also affect spindle orientation (Kitagawa et al 2011b;Brito et al 2012).…”