Drosophila neuroblasts as a new model for the study of stem cell self-renewal and tumour formation.

Song Li,Casper Groth,Hongyan Wang

doi:10.1042/bsr20140008

Abstract

Drosophila larval brain stem cells (neuroblasts) have emerged as an important model for the study of stem cell asymmetric division and the mechanisms underlying the transformation of neural stem cells into tumour-forming cancer stem cells. Each Drosophila neuroblast divides asymmetrically to produce a larger daughter cell that retains neuroblast identity, and a smaller daughter cell that is committed to undergo differentiation. Neuroblast self-renewal and differentiation are tightly controlled by a set of intrinsic factors that regulate ACD (asymmetric cell division). Any disruption of these two processes may deleteriously affect the delicate balance between neuroblast self-renewal and progenitor cell fate specification and differentiation, causing neuroblast overgrowth and ultimately lead to tumour formation in the fly. In this review, we discuss the mechanisms underlying Drosophila neural stem cell self-renewal and differentiation. Furthermore, we highlight emerging evidence in support of the notion that defects in ACD in mammalian systems, which may play significant roles in the series of pathogenic events leading to the development of brain cancers.

Highlights

Apical–basal polarity During asymmetric divisions, neuroblasts are polarized to form distinct cortical domains, containing different sets of proteins that are segregated into two different daughter cells by a neural stem cell self-renewal mechanism conserved throughout the embryonic and larval stages
Much of our basic knowledge about the molecular machinery controlling neural stem cell homoeostasis and asymmetric cell division (ACD) has been gained from Drosophila neuroblasts
With the identification of the type II neuroblast lineages in Drosophila that are analogous to mammalian neural stem cell lineages, we anticipate that unravelling the molecular machinery controlling the self-renewal and differentiation of type II neuroblasts and intermediate neural progenitor (INP) will provide valuable insights relevant to our understanding of mammalian neural stem cell biology and the pathological processes involved in neural stem cell-dependent brain tumour formation and disease progression

Summary

DISRUPTION OF ASYMMETRIC DIVISION AND BRAIN TUMOUR FORMATION

Apical–basal polarity During asymmetric divisions, neuroblasts are polarized to form distinct cortical domains, containing different sets of proteins that are segregated into two different daughter cells by a neural stem cell self-renewal mechanism conserved throughout the embryonic and larval stages. A common regulator between the two distinct stem cell populations is the Notch pathway inhibitor Numb [27,28,48] This protein plays a pivotal role by enabling binary cell fate specification events to occur as a result of its asymmetric sequestration in post-mitotic neurons [28,88,90], How Numb exert its inhibitory function on Notch signalling remains poorly understood. Among the identified Notch targets in Drosophila are a number of genes encoding bHLH-O (basic helix-loop-helix-orange) transcription factors, implicated in controlling neurogenesis by acting as neural differentiation repressors, including neuroblast marker Dpn (Deadpan) and members of the Enhancer of split complex, E(spl) [89,103]. This further emphasizes the importance of the link between protein polarity and ACD in neurogenesis

MAMMALIAN STUDIES OF ASYMMETRIC DIVISION AND HUMAN CANCERS

CONCLUSIONS AND FUTURE PERSPECTIVES