Regulating neural proliferation in the Drosophila CNS
Introduction
Understanding how the rich diversity of different neuronal and glial types is generated is a central theme in developmental neurobiology (see reviews in this issue by T. Lee and H. Sawa). An equally important question relates to how the numbers of each cell type are regulated and, more generally, how overall brain size is specified. Here we review recent progress in this second area, focusing on cell proliferation in the CNS of the fruit fly, Drosophila. This provides a powerful model system in which to observe neural stem cells in action and to screen for the genes underlying their remarkable properties.
The anatomy of the developing Drosophila CNS can be divided into the optic lobes (OL), the central brain (CB) and the ventral nerve cord (VNC). The CB contains olfactory learning and memory centres known as the mushroom bodies (MB) and the VNC is further subdivided into 3 thoracic (Th) and 9 abdominal (Ab) neuromeres (Figure 1). The cells that generate the neurons and glia in all of these CNS regions are neural stem-cell-like progenitors called neuroblasts. These multipotent cells are specified from ectodermal epithelia by a process involving proneural genes and Notch signalling. The CB and VNC neuroblasts derive from the ventral neuroectoderm of the early embryo, whereas OL neuroblasts form later on, during larval life, from neuroepithelial placodes (reviewed by [1, 2]). In the forming VNC, there are ∼30 neuroblasts per hemi-neuromere, which delaminate internally in a stereotypical pattern. Neuroblasts then go through numerous asymmetric self-renewing divisions, each time producing an intermediate progenitor called a ganglion mother cell (GMC). In turn, GMCs divide only once to yield two postmitotic cells that can be neurons or glia. Each of the ∼30 VNC neuroblasts is unique in that it expresses different dorsoventral and anteroposterior patterning genes and generates a unique embryonic lineage of neurons and glia [3, 4, 5, 6, 7]. Although the short embryonic phase of neuroblast divisions is sufficient to form the functioning CNS of the larva, it only contributes ∼10% of the neurons in the adult CNS. A long postembryonic phase of progenitor divisions, involving the continued activity of most (but not all) of the original embryonic neuroblasts accounts for the remaining ∼90% of adult neurons [8, 9, 10, 11, 12]. Postembryonic neuroblast divisions are highly region specific, with a general bias for anterior domains to retain a larger fraction of the original number of embryonic neuroblasts and for each one to divide more times than in posterior domains (reviewed by [13]). This leads to dramatic anterior expansion of the CNS during larval/pupal stages, in line with the anterior locations of major adult-specific sensorimotor structures such as eyes, wings and legs.
Section snippets
The nuts and bolts of a neuroblast
Neuroblasts utilise two different molecular machines that endow them with stem-cell-like properties. The first of these corresponds to asymmetrically localised protein complexes that direct one daughter cell to self-renew whereas the other becomes a GMC. The second molecular machine comprises a set of sequentially expressed transcription factors that allow each neuroblast to make an invariant series of different GMC identities, and thus different types of neurons/glia.
Many molecular components
How many different types of postembryonic neuroblasts are there?
In contrast to embryonic stages, the repertoire of neuronal/glial types generated by each neuroblast during postembryonic development has yet to be clearly defined for most CNS regions. Exceptions are MB and antennal-lobe neuroblasts where multiple different neuronal types produced in a stereotypical order have been defined systematically [38, 39]. In addition, a systematic study of Th neuroblasts has identified 24 different lineages per hemisegment based on their position and the morphology of
Most neuroblasts undergo reversible quiescence
Late in embryogenesis, the majority of neuroblasts in the CB and VNC enter a reversible G1 arrest known as quiescence [9]. This separates the embryonic and postembryonic phases of neurogenesis. The only postembryonic neuroblasts that do not undergo quiescence are the four MB neuroblasts, which generate very large lineages of ∼500 neurons each, and one less-well characterised ventrolateral CB neuroblast [11, 12, 39].
Neuroblast quiescence is known to be regulated by several different intrinsic
Increasing progenitor numbers via a symmetric division strategy
The most dramatic cell proliferation within the postembryonic CNS occurs within the OL. The embryonic OL primordium invaginates in the early embryo as a placode of 30–40 neuroepithelial cells. This expands dramatically during postembryonic stages by symmetric divisions, segregating into two separate epithelia known as the Inner Proliferation Centre (IPC) and the Outer Proliferation Centre (OPC). Most OL neurons are generated from these two centres although smaller numbers are also generated
Increasing progenitor numbers via an asymmetric division strategy
Recently, a second strategy was discovered for expanding progenitor numbers (and thus neuronal numbers), this time utilising a modified form of asymmetric division. In the dorso-posterior medial part of the postembryonic CB, eight primary neuroblasts (probably the pl and pm subgroups) divide asymmetrically to self-renew and bud off intermediate neural progenitors (INPs) that, unlike GMCs, can undergo multiple divisions [20••, 55, 56••, 57••]. We now refer to these atypical primary progenitors
Mechanisms for terminating neuroblast divisions
The time at which neuroblasts finally and irreversibly stop dividing is crucial, not only for achieving the correct balance of early versus late-born neuronal/glial fates but also for determining the final size of the growing CNS. This neuroblast termination process occurs at very different times in different regions but is complete by the end of metamorphosis, such that there are no identifiable neuroblasts in the adult CNS [12]. We now discuss what is known about the molecular mechanisms
Conclusions and future directions
An important conclusion from recent studies is that the formation and mode of division of Drosophila neuroblasts are more diverse than previously thought. Symmetric expansion of neuroepithelial cells facilitates local increases in neuroblast number and the ‘classic’ asymmetric neuroblast lineage can be adapted to make more cells via INPs. In addition, some types of neuroblasts enter quiescence whereas others do not, some neuroblasts finally terminate their divisions via apoptosis yet others
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We apologise to those of our colleagues whose work was not cited owing to space constraints. We thank Iris Salecker, Andrea Brand and an anonymous reviewer for critical reading of the manuscript and Wai Han Yau for help with illustrations. R.S-N., L.Y.C. and A.P.G. are supported by the Medical Research Council and a grant to R.S-N. from the Portuguese Foundation for Science and Technology.
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Development of the Drosophila melanogaster embryonic CNS
2020, Patterning and Cell Type Specification in the Developing CNS and PNS: Comprehensive Developmental Neuroscience, Second EditionFrom Early to Late Neurogenesis: Neural Progenitors and the Glial Niche from a Fly's Point of View
2019, NeuroscienceCitation Excerpt :It is during the larval stage when they exit quiescence in a nutrition-dependent manner to start the second wave of neurogenesis (Chell and Brand, 2010; Sousa-Nunes et al., 2011; Speder et al., 2011; Lanet et al., 2013), generating the more complex CNS required for adult life. Unlike in the embryo, the VNC in larval stages consists of only type I NBs (Figs. 2C and 3C) while the larval CB has type I, type II, MB and antennal lobe (AL) NBs (Das et al., 2013; Doe, 2017; Homem and Knoblich, 2012; Sousa-Nunes et al., 2010; Figs. 2A and 3A). In larvae, type I NB cells, which are reactivated following the embryonic stage, are Deadpan (Dpn)+ Asense (Ase)+ Pointed 1 (PntP1; Pnt)− and produce GMCs that are Dpn− Prospero (Pros)+ (Zhu et al., 2011; Xie et al., 2016).
Drosophila homolog of the intellectual disability-related long-chain acyl-CoA synthetase 4 is required for neuroblast proliferation
2019, Journal of Genetics and GenomicsCitation Excerpt :Neural stem cells in Drosophila brain are called neuroblasts (Nbs). The Nbs in the central brain are classified into type I, type II and mushroom body (MB) Nbs according to their location and lineage characteristics (Sousa-Nunes et al., 2010). During neurogenesis, type I and MB Nbs undergo asymmetric cell division to self-renew and generate a series of smaller daughter cells called ganglion mother cells (GMCs), each of which divides only once to produce a pair of post-mitotic neurons or glial cells (Sousa-Nunes et al., 2010).