Centrosome-centric view of asymmetric stem cell division

Abstract

The centrosome is a unique organelle: the semi-conservative nature of its duplication generates an inherent asymmetry between 'mother' and 'daughter' centrosomes, which differ in their age. This asymmetry has captivated many cell biologists, but its meaning has remained enigmatic. In the last two decades, many stem cell types have been shown to display stereotypical inheritance of either the mother or daughter centrosome. These observations have led to speculation that the mother and daughter centrosomes bear distinct information, contributing to differential cell fates during asymmetric cell divisions. This review summarizes recent progress and discusses how centrosome asymmetry may promote asymmetric fates during stem cell divisions.

Keywords: asymmetric stem cell division; centrosomes; stem cell.

Figure 1.

The centrosome duplication cycle in animal cells. At the beginning of the G1 phase of the cell cycle, cells contain a single centrosome that is composed of two centrioles that are orthogonally aligned with each other, surrounded by pericentriolar material (PCM). The mother centriole (orange) served as a template to assemble the daughter centriole (blue) in the previous cell cycle, and can be distinguished from the daughter by its distal and subdistal appendages. Prior to the G1-S transition, the tight juxtaposition of the mother and daughter centrioles is resolved (centriole disengagement) but they remain connected by a fibrous structure called the tether. At the G1-S transition, each centriole initiates the nucleation of new daughter centrioles (green), and the daughter centriole becomes the mother for the first time, but it is not yet mature enough to gain appendages. The new daughter centrioles elongate fully by late G2 phase, and two centrosomes (each containing mother and daughter centrioles) separate from each other prior to mitotic entry. In mitosis, the mother and daughter centrosomes organize the mitotic spindle and segregate into the two daughter cells.

Figure 2.

Centrosome inheritance during asymmetric stem cell division. (a) Drosophila male germline stem cells (GSCs) divide asymmetrically under the influence of signals derived from the hub cells, which function as the stem cell niche. The mother centrosome is anchored at the adherens junctions formed between the GSCs and the hub and orients the GSC mitotic spindle. Upon division, the mother centrosome is always inherited by the GSCs. (b) Drosophila neuroblasts (NBs) divide asymmetrically by polarizing fate determinants (e.g. Numb, Prospero (Pros) and Miranda (Mira)) at the basal cortex, which are subsequently segregated to differentiating cells (ganglion mother cells). Polarization of these fate determinants and spindle orientation is governed by the apical polarity complexes (e.g. Par3/Par-6/aPKC complex, Pins and Insc). The daughter centrosome is always inherited by the NBs upon division.

Figure 3.

Function of centrosome asymmetry in asymmetric cell division. (a) During early embryonic development of the mollusc IIyanassa, fate-determining mRNAs associate with the centrosome and segregate asymmetrically to one of two daughter cells. Lower panel: An example of asymmetric segregation of mRNAs. Image adapted from [49]. (b) During mouse brain development, centrosome asymmetry leads to a biased reception of signals between two daughter cells in asymmetrically dividing apical progenitors (APs). The mother centrosome is associated with the ciliary membrane remnant, allowing the cell to reassemble the cilia quickly upon mitotic exit and to retain the stem cell character. The sibling cell that inherited the daughter centrosome, which lacks the remnant ciliary membrane, takes longer to build the cilium and enters the differentiation programme. (c) The aggresome is associated with one centrosome and segregates asymmetrically during mitosis in multiple mammalian cell types including human embryonic stem cells (ESCs). Lower panel: An example of asymmetric segregation of the aggresome. Image adapted from [50].

Figure 4.

Proteins that exhibit stem cell-specific centrosomal localization and their functions. (a) Protein localization of Klp10A, Alms1a and Ninein in Drosophila stem cells. Images from [–70]. (b) Phenotypes upon knockdown of klp10A and alms1a. klp10A depletion leads to elongation of the mother centrosomes in Drosophila male GSCs. Depletion of alms1a leads to a loss of the daughter centrosomes and elongation of the mother centrosome. Asl marks centrosomes, Vasa germ cells and FasIII hub cells (also marked by asterisks).