The Tumor Suppressors Brat and Numb Regulate Transit-Amplifying Neuroblast Lineages in Drosophila

Abstract

In both vertebrates and insects, neurons typically arise from neural stem cells or terminally dividing intermediate progenitors. Here, we describe another mode of neurogenesis where neural stem cells generate secondary precursors that undergo multiple rounds of self-renewing transit-amplifying divisions. We identify the Posterior Asense-Negative (PAN) neuroblasts, which do not express the transcription factors Asense or Prospero. PAN neuroblasts rely on the segregating determinants Numb and Brat to generate smaller, secondary neuroblasts that in turn give rise to ganglion mother cells (GMCs) and neurons throughout larval development. In brat or numb mutants, misspecified secondary neuroblasts are unable to produce differentiated progeny and initiate tumor-like overgrowth. In prospero mutants, however, tumors arise from GMCs while secondary neuroblasts are correctly specified. Our data describe a transit-amplifying lineage in the Drosophila nervous system and suggest that different vulnerabilities in intermediate cell types can affect the outcome of tumor suppressor loss in stem cell lineages.

Insights into brain development and disease from neurogenetic analyses in Drosophila melanogaster

“…All of these neurons derive from a restricted set of neural stem cell-like progenitors, called neuroblasts, which originate in the neuroectoderm of the early embryo (Urbach and Technau 2004;Doe 2008;Knoblich 2008;Egger et al 2008;Reichert 2011;Homem and Knoblich 2012 Technau et al 2006). In this manner positional information is imparted to the cells of the neuroectoderm in the form of a combinatorial gene expression code (figure 1).…”

“…These large primary progenitor cells are highly proliferative and typically undergo multiple rounds of asymmetric cell divisions, in which they self-renew and at the same time generate a smaller daughter cell called a GMC which divides once to produce two postmitotic neural cells (Doe 2008;Knoblich 2008;Egger et al 2008;Reichert 2011). Due to its delamination from the neuroectoderm, each neuroblast largely retains the gene expression pattern of the neuroectodermal region from which it derives.…”

“…In contrast, in Drosophila, a great deal is known about the molecular mechanisms underlying neural stem cell proliferation during normal development, and powerful genetic and genomic tools are available to investigate how the misregulation of these mechanisms might result in brain tumour formation. In the last decade, a number of studies have shown that defects in the molecular control of asymmetric cell division of neuroblasts can result in uncontrolled proliferation and tumorigenesis ( Knoblich 2008Knoblich , 2010). An apical complex is required for maintenance of polarity and spindle orientation as well as for segregation of cell fate determinants of a basal complex into the smaller daughter cell.…”

Opportunities lost and gained: Changes in progenitor competence during nervous system development

“…13,14,15,32 Type II neuroblasts divide asymmetrically to generate a series of INPs that produce an average of 10 neurons each, whereas larval type I neuroblasts make GMCs that only produce a pair of neurons. 13,14,15 How do type II neuroblasts generate INPs rather than GMCs?…”

“…2c). 13,14,15 In this section, we will discuss how (a) embryonic type I neuroblasts lose competence to respond to early temporal transcription factors due to changes in subnuclear gene position, (b) larval type I neuroblasts lose competence to respond to oncogenic mutations, (c) larval INPs lose competence to respond to Notch signaling, (d) larval type II neuroblasts use Trithorax to maintain competence to generate INPs, and (e) sensory neuron progenitors change competence to respond to Notch signaling.…”