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Role of Notch Signaling in Establishing the Hemilineages of Secondary Neurons in Drosophila Melanogaster James W

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Role of Notch Signaling in Establishing the Hemilineages of Secondary Neurons in Drosophila Melanogaster James W RESEARCH ARTICLE 53 Development 137, 53-61 (2010) doi:10.1242/dev.041749 Role of Notch signaling in establishing the hemilineages of secondary neurons in Drosophila melanogaster James W. Truman*,§, Wanda Moats, Janet Altman*, Elizabeth C. Marin† and Darren W. Williams‡ SUMMARY The secondary neurons generated in the thoracic central nervous system of Drosophila arise from a hemisegmental set of 25 neuronal stem cells, the neuroblasts (NBs). Each NB undergoes repeated asymmetric divisions to produce a series of smaller ganglion mother cells (GMCs), which typically divide once to form two daughter neurons. We find that the two daughters of the GMC consistently have distinct fates. Using both loss-of-function and gain-of-function approaches, we examined the role of Notch signaling in establishing neuronal fates within all of the thoracic secondary lineages. In all cases, the ‘A’ (NotchON) sibling assumes one fate and the ‘B’ (NotchOFF) sibling assumes another, and this relationship holds throughout the neurogenic period, resulting in two major neuronal classes: the A and B hemilineages. Apparent monotypic lineages typically result from the death of one sibling throughout the lineage, resulting in a single, surviving hemilineage. Projection neurons are predominantly from the B hemilineages, whereas local interneurons are typically from A hemilineages. Although sibling fate is dependent on Notch signaling, it is not necessarily dependent on numb, a gene classically involved in biasing Notch activation. When Numb was removed at the start of larval neurogenesis, both A and B hemilineages were still generated, but by the start of the third larval instar, the removal of Numb resulted in all neurons assuming the A fate. The need for Numb to direct Notch signaling correlated with a decrease in NB cell cycle time and may be a means for coping with multiple sibling pairs simultaneously undergoing fate decisions. KEY WORDS: Neurogenesis, Hemilineage, Notch, Numb, Neuroblasts, Drosophila INTRODUCTION is determined by a sequence of transcription factors that are passed How such a great diversity of cell types is generated within the on to successive GMCs through time and establish neuronal fates nervous system during development remains a major unresolved within a given lineage (Kambadur et al., 1998; Isshiki et al., 2001; question in neurobiology. In vertebrates and invertebrates, both Grosskortenhaus et al., 2005). In the embryo, the daughter neurons inductive (Briscoe, 2009; Edlund and Jessell, 1999) and lineage- produced by the GMC division typically have distinct identities, and based mechanisms are involved in producing this diversity (Desai this difference is controlled by Notch signaling (Spana and Doe, and McConnell, 2000; Cayoutte et al., 2006), but different regions 1996; Skeath and Doe, 1998). of the nervous system may be biased towards one end of this The bulk of the activity of most NBs is devoted to making spectrum or the other. Within insects, lineage-based mechanisms are secondary neurons. The secondary neurons constitute a more responsible for the vast majority of neuronal diversity, with the homogeneous population than the initial, primary set. In insects with possible exception of the optic lobes. In the central brain and ventral complete metamorphosis, like Drosophila, most of the secondary ganglia, the neuronal stem cells (the neuroblasts, NBs) are neurons are born during a larval phase of neurogenesis. Studies on identifiable as individuals and each makes a characteristic set of the generation of secondary neurons in the caterpillar of the tobacco progeny (e.g. Bossing et al., 1996; Schmidt et al., 1997; Schmid et hornworm, Manduca sexta (Witten and Truman, 1991), indicated al., 1999). NBs go through asymmetric, self-renewing divisions, that the GMC divides to make daughters of divergent phenotypes each resulting in a neuronal precursor cell, the ganglion mother cell and that this process is then reiterated scores of times to generate two (GMC). Although there are now known to be exceptions (Bello et major classes of interneurons. Similarly, in grasshoppers, Jia and al., 2008; Bowman et al., 2008; Boone and Doe, 2008), the GMC Siegler (Jia and Siegler, 2002) showed that the GMCs from the usually undergoes a terminal division, producing two daughter median neuroblast in the thorax consistently produce an engrailed neurons. The initial progeny made by a NB are often highly diverse positive and engrailed negative daughter, which become a local and are termed the primary neurons (Hartenstein et al., 2008). Their interneuron and a projection cell, respectively. Region-specific cell identities are based on the birth order of the GMCs, and this ordering death of one sibling then sculpts the final lineage composition in a given segment. These examples of diverse classes of cells being generated throughout a lineage is in contrast to neurogenesis in the Department of Biology, Box 351800, University of Washington, Seattle, WA 98195, mushroom bodies, where sibling neurons generated at any given USA. time are morphologically indistinguishable (Lee et al., 1999). *Present address: Janelia Farm Research Campus, Howard Hughes Medical Institute, In this paper, we present a comprehensive analysis of the role of 19700 Helix Drive, Ashburn, VA 20147, USA Notch signaling in generating neuronal phenotypes within the †Present address: Department of Biology, Bucknell University, Lewisburg, PA 17837, USA secondary lineages of the segmental central nervous system (CNS). ‡Present address: MRC Centre for Developmental Neurobiology, King’s College The universal pattern is for a GMC to produce two neurons of London, Guy’s Hospital Campus, London SE1 1UL, UK different phenotypes, ‘A’ and ‘B’, with cell death involved in making §Author for correspondence ([email protected]) some lineages monotypic. A clear division of phenotype between Accepted 24 October 2009 these A and B cell types suggest that the circuitry of the thoracic DEVELOPMENT 54 RESEARCH ARTICLE Development 137 (1) nervous system is generated in developmental units we term secondary neurons produced during the postembryonic neurogenic ‘hemilineages’. The accompanying paper by Lin et al. (Lin et al., phase are much more homogeneous (Truman et al., 2004; Pereanu 2010) shows that this pattern also holds the antennal lobes in the brain. and Hartenstein, 2006; Brown and Truman, 2009; Zhou et al., 2009). As seen in Fig. 1A, a NB typically generates either one or two classes MATERIALS AND METHODS of secondary neurons, as defined by their pattern of neurite Fly stocks projection. In the latter case, the two classes are based the division of Flies were reared on the standard yeast-cornmeal-molasses diet. Mitotic the GMC, with the two daughters showing distinct growth decisions clones were generated using the mosaic analysis using a repressible cell (Fig. 1B). This difference is then repeated for all of the GMCs marker (MARCM) technique (Lee and Luo, 1999). We used the pan- neuronal driver, elavC155 GAL4 (Lin and Goodman, 1994) to obtain a range generated during the second neurogenic phase. Skeath and Doe of clones that covered all of the thoracic lineages. Wild-type clones were showed that Notch signaling is responsible for the differences in generated in flies of the genotype: GAL4C155, hsFLP, UAS-mCD8::GFP; sibling fates during GMC divisions in the embryo (Skeath and Doe, FRT2A, tubP-GAL80/FRT2A. Notch null clones were produced using the 1998), and we hypothesized that this mechanism probably also null allele N55e11 (Heitzler and Simpson, 1991) in the genotype: extends into the secondary phase of neurogenesis. Immunostaining elavC155,N55e11,FRT 19A/tub-GAL80, hs-flp, FRT 19A; UAS- of neuroblast clones for Notch showed the prominent membrane mCD8::GFP/UAS-mCD8::GFP. Clones that showed constitutive Notch localization of Notch in the NB, GMCs and an adjacent cluster of signaling were produced by expressing the intracellular domain of Notch young neurons (Fehon et al., 1991), but also, typically, two of the CA C155 [UAS-Notch (Larkin et al., 1996)] using the genotype: elav , FRT young neurons had nuclear Notch (Fig. 1C,D) suggesting that these 19A/tub-GAL80, hs-flp, FRT 19A; UAS-mCD8::GFP/UAS-mCD8::GFP; were in the process of establishing their sibling fates. Therefore, we UAS-NotchCA/+. Numb activity was removed using the numb2 null allele (Frise et al., 1996) in the combination: elavC155, UAS-mCD8::GFP, hs- examined Notch signaling in the secondary lineages using both loss- flp/elavC155, UAS-mCD8::GFP, hs-flp; tub-GAL80, FRT 40A/y+,numb2, ck, of-function and gain-of-function approaches. FRT40A. Cell death was inhibited in homozygous clones that were mutant MARCM clones were induced postembryonically to include only for the initiator caspase dronc (Kondo et al., 2006; Williams et al., 2006) the secondary neurons born during the larval neurogenic period. using flies of the following genotype: hs-flp, elavC155GAL4, UAS- Notch loss-of-function clones were homozygous mutant for the null mCD8::GFP/+; tubP-GAL80, FRT 2A/droncDA8, FRT2A. allele N55e11 (Heitzler and Simpson, 1991). During Notch signaling For inducing MARCM clones in recently hatched larvae, eggs were the receptor is cleaved and the intracellular domain translocated to collected over a 1- to 2-hour period, maintained at 25°C for 24 hours, and the nucleus (Struhl et al., 1993). We generated Notch gain-of- the larvae then heat-shocked at 37°C for 45 minutes to 1 hour. Brief egg function clones either by expressing the intracellular domain of collections were also maintained for 72 hours before heat shock to induce Notch, which serves as a constitutive activator [NotchCA (Larkin et clones around the start of the third larval instar. al., 1996)], or by making MARCM clones that were null for numb, Immunocytochemistry a negative regulator of Notch (Knoblich et al., 1995; Spana and Doe, Dissected nervous systems were fixed in buffered 3.7% formaldehyde for 1996). Fig. 2 summarizes the effects of manipulating Notch about an hour at room temperature and then washed three times in PBS-TX signaling in the 25 secondary lineages in the ventral CNS.
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