Polarization of Drosophila neuroblasts during asymmetric division

Abstract

During Drosophila development, neuroblasts divide to generate progeny with two different fates. One daughter cell self-renews to maintain the neuroblast pool, whereas the other differentiates to populate the central nervous system. The difference in fate arises from the asymmetric distribution of proteins that specify either self-renewal or differentiation, which is brought about by their polarization into separate apical and basal cortical domains during mitosis. Neuroblast symmetry breaking is regulated by numerous proteins, many of which have only recently been discovered. The atypical protein kinase C (aPKC) is a broad regulator of polarity that localizes to the neuroblast apical cortical region and directs the polarization of the basal domain. Recent work suggests that polarity can be explained in large part by the mechanisms that restrict aPKC activity to the apical domain and those that couple asymmetric aPKC activity to the polarization of downstream factors. Polarized aPKC activity is created by a network of regulatory molecules, including Bazooka/Par-3, Cdc42, and the tumor suppressor Lgl, which represses basal recruitment. Direct phosphorylation by aPKC leads to cortical release of basal domain factors, preventing them from occupying the apical domain. In this framework, neuroblast polarity arises from a complex system that orchestrates robust aPKC polarity, which in turn polarizes substrates by coupling phosphorylation to cortical release.

Figure 1.

The Drosophila neuroblast. (A) Embryonic neuroblasts form from the neuroepithelium where they delaminate, inheriting the polarity from the tissue from which they are born. (B) Once delaminated, neuroblasts round up, grow larger, and undergo repeated asymmetric cell divisions. Each division yields a self-renewed neuroblast and ganglion mother cell (GMC), which divides once more to populate the central nervous system.

Figure 2.

Neuroblast polarity. (A) At metaphase, neuroblasts localize factors that specify differentiation to the basal cortical domain. The apical domain contains factors that keep the GMC fate determinants in the basal domain and ensure self-renewal. (B) By telophase, each cortical domain extends to the cleavage furrow, but does not pass, ensuring proper fate determinant segregation. (C) Following division, fate determinants such as Prospero are released from the cortex and enter the nucleus to change the pattern of gene expression.

Figure 3.

Cortical targeting of apical and basal domain constituents. (A) Hierarchy of cortical localization for basal domain proteins. (B) Phosphorylation-mediated cortical displacement model for polarization of fate determinants by aPKC. In this model, the apical aPKC domain phosphorylates basal domain factors that enter the apical domain (e.g., by diffusion), causing them to be released from the cortex. The mechanism by which this cycle is completed is unknown. (C) Hierarchy of cortical localization for apical domain proteins.

Figure 4.

Regulation of aPKC polarity and activity. (A) Domain structure of Par complex proteins. PDZ (PSD-95, Dlg, and ZO-1); PS (pseudosubstrate); NTD (amino-terminal domain); AID (aPKC interaction domain); C1 (cysteine-rich domain type 1); PB1 (Phox Bem1 domain). Arrows denote domain interactions that assemble the complex. (B) Pathway for regulation of aPKC polarity and effect on substrates. Solid lines denote direct interactions, whereas dashed lines indicate that intermediates may be present.