Asymmetric Cell Division and Notch Signaling Specify Dopaminergic Neurons in Drosophila

Abstract

In Drosophila, dopaminergic (DA) neurons can be found from mid embryonic stages of development till adulthood. Despite their functional involvement in learning and memory, not much is known about the developmental as well as molecular mechanisms involved in the events of DA neuronal specification, differentiation and maturation. In this report we demonstrate that most larval DA neurons are generated during embryonic development. Furthermore, we show that loss of function (l-o-f) mutations of genes of the apical complex proteins in the asymmetric cell division (ACD) machinery, such as inscuteable and bazooka result in supernumerary DA neurons, whereas l-o-f mutations of genes of the basal complex proteins such as numb result in loss or reduction of DA neurons. In addition, when Notch signaling is reduced or abolished, additional DA neurons are formed and conversely, when Notch signaling is activated, less DA neurons are generated. Our data demonstrate that both ACD and Notch signaling are crucial mechanisms for DA neuronal specification. We propose a model in which ACD results in differential Notch activation in direct siblings and in this context Notch acts as a repressor for DA neuronal specification in the sibling that receives active Notch signaling. Our study provides the first link of ACD and Notch signaling in the specification of a neurotransmitter phenotype in Drosophila. Given the high degree of conservation between Drosophila and vertebrate systems, this study could be of significance to mechanisms of DA neuronal differentiation not limited to flies.

Formation and specification of a Drosophila dopaminergic precursor cell

“…Interestingly, most of these neurons are collinear with the H-cell suggesting that the same segmentation genes that control H-cell development also play a role in paramedial and dorsal lateral neuron development. Consistent with this view, recent work (Tio et al, 2011) has indicated that both DA neurons are wg + , which overlaps in lateral CNS expression with gsb and slp1/2 , L(1)sc is ectopically present in MP1 neurons (blue arrow; only one MP1 neuron is shown), as well as in the H-cell and H-cell sib (yellow arrows) and AMG (white asterisks).…”

Essential role of grim-led programmed cell death for the establishment of corazonin-producing peptidergic nervous system during embryogenesis and metamorphosis in Drosophila melanogaster

“…Spana and Doe, 1996; Tio et al, 2011). In the NB7-3 lineage, daughter cells of the GMC-1 also take distinct fates, one interneuron (EW1) and the other motor neuron (GW), depending on the inheritance of Numb.…”

Uncovering the link between malfunctions in Drosophila neuroblast asymmetric cell division and tumorigenesis

“…The first study to show the link between both asymmetric division machinery and Notch signaling and specification of a neurotransmitter neuronal phenotype was performed in Drosophila by Tio et al [21]. Findings from this study showed that loss of function of the proteins Inscuteable and Bazooka resulted in an excess number of dopaminergic neurons.…”

“…Findings from this study showed that loss of function of the proteins Inscuteable and Bazooka resulted in an excess number of dopaminergic neurons. On the other hand, loss of function of basally distributed proteins such as Numb resulted in a reduction of dopaminergic neurons [21]. Additionally, loss of Notch signaling results in an excess amount of this neuronal phenotype, and vice versa.…”