Brat Is a Miranda Cargo Protein that Promotes Neuronal Differentiation and Inhibits Neuroblast Self-Renewal

Abstract

An important question in stem cell biology is how a cell decides to self-renew or differentiate. Drosophila neuroblasts divide asymmetrically to self-renew and generate differentiating progeny called GMCs. Here, we report that the Brain tumor (Brat) translation repressor is partitioned into GMCs via direct interaction with the Miranda scaffolding protein. In brat mutants, another Miranda cargo protein (Prospero) is not partitioned into GMCs, GMCs fail to downregulate neuroblast gene expression, and there is a massive increase in neuroblast numbers. Single neuroblast clones lacking Prospero have a similar phenotype. We conclude that Brat suppresses neuroblast stem cell self-renewal and promotes neuronal differentiation.

Somatic stem cells and the origin of cancer

“…Normally, Drosophila neuroblasts divide asymmetrically, a process which is controlled by genes regulating cell polarity and cell fate 106,107 . Using Drosophila as a model, three recent studies have shown that the loss of polarity and impairment of asymmetric division in stem cells leads to tumorigenesis [108][109][110] . In these reports, neuroblasts containing mutations in various genes that control cell division (Raps, Mira, Numb, Brat and Pros) developed aggressive tumors that could be retransplanted into new hosts.…”

“…In these reports, neuroblasts containing mutations in various genes that control cell division (Raps, Mira, Numb, Brat and Pros) developed aggressive tumors that could be retransplanted into new hosts. Importantly, asymmetric division was disrupted in mutant stem cells, whereby both daughter cells grow and behave like neuroblasts leading to the formation of tumors [108][109][110] . This transformation was associated with genome instability and centrosome alterations ( fig.…”

Regulation of the Drosophila lin‐41 homologue dappled by let‐7 reveals conservation of a regulatory mechanism within the LIN‐41 subclade

“…They have been shown to participate in numerous distinct processes, including roles in development, both normal and tumorous, asymmetric cell divisions and viral response (Arama et al, 2000;Horn et al, 2004;Bello et al, 2006;Betschinger et al, 2006;Lee et al, 2006;Sakuma et al, 2007) and see Table 2 in Meroni and Diez-Roux (2005), to name but a few. This protein superfamily is characterized by the presence of multiple protein-protein interaction domains, from which it has derived its name, that is, RING, B-box, and coiled-coil domains (Fig.…”

“…BRAT, on the other hand, has been the subject of intense study in recent times (Bello et al, 2006;Betschinger et al, 2006;Lee et al, 2006) and as the name suggests, gives rise to brain tumours when mutated (Woodhouse et al, 1998;Arama et al, 2000). Tumours arising in brat animals are highly proliferative, invasive, transplantable and lethal to the animal (Woodhouse et al, 1998).…”

“…Of interest, tumorigenic alleles of brat disrupt the NHL repeat region, implicating it as having a direct role in tumor suppression (Arama et al, 2000;Loop et al, 2004). Furthermore, the BRAT NHL domain has been shown to mediate protein-protein interactions of various kinds (Sonoda and Wharton, 2001;Frank et al, 2002), including direct binding to and promoting asymmetric distribution of the cell fate determinant Prospero (Bello et al, 2006;Betschinger et al, 2006;Lee et al, 2006). Thus, both dpld and brat can cause tumors when mutated, suggesting at least some functional overlap.…”