Asymmetric stem cell division: Lessons from Drosophila

Abstract

Asymmetric cell division is an important and conserved strategy in the generation of cellular diversity during animal development. Many of our insights into the underlying mechanisms of asymmetric cell division have been gained from Drosophila, including the establishment of polarity, orientation of mitotic spindles and segregation of cell fate determinants. Recent studies are also beginning to reveal the connection between the misregulation of asymmetric cell division and cancer. What we are learning from Drosophila as a model system has implication both for stem cell biology and also cancer research.

Introduction

Early studies on ascidian and leech cell lineages more than one century ago first postulated that the asymmetric distribution of cell substances in cell division might affect cell fate [1], [2]. In Drosophila the molecular basis of asymmetric cell division began to be unravelled with the discovery of the cell fate determinant Numb in sensory organ precursors (SOP) and its role in cellular identity specification [3]. Since then this topic has been intensively studied and considerable insights have been gained from many laboratories using different model systems including the Caenorhabditis elegans zygote, Drosophila neuroblasts, sensory organ precursors, and more recently, germline stem cells (GSCs), as well as mammalian neuroepithelial cells [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]. Given the cancer stem cell hypothesis [14], [15], [16], the study of asymmetric cell division is likely to contribute to our understanding of stem cell biology and cancer biology.

Stem cells are unique in their ability to self-renew and to produce daughter cells committed to differentiation. In addition, they use a balance of symmetric and asymmetric cell divisions to regulate the number of stem cells and differentiated cells. Symmetric divisions lead to two identical daughter cells, whereas following an asymmetric cell division the smaller of the two daughter cells differentiates. It is crucial for stem cells to tightly control this choice between symmetric proliferative divisions and asymmetric differentiative divisions during development and tissue repair because, if cellular homeostasis is not maintained, premature differentiation may lead to incomplete tissue or organ development, whereas uncontrolled proliferation can lead to tumour formation [16].

In this review we summarise recent key discoveries in this field mostly from Drosophila neural stem cells, or neuroblasts (NB). Our main goal is to describe the machinery that orchestrates asymmetric NB division during development. We focus on the establishment of cell polarity, the regulation of mitotic spindle orientation, centrosome asymmetry and the asymmetric segregation of cell fate determinants. And we explore how this affects the proliferation and differentiation of the generated daughter cells. We also briefly discuss how asymmetrically dividing NBs arise from symmetrically dividing neuroepithelial cells and what mechanisms might be involved in the switch from symmetric to asymmetric division. In the last part of the review, we discuss the link between asymmetric cell division and tumour formation, as recent evidence from Drosophila shows that the impairment of asymmetric cell division can lead to tumourigenesis [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28].