Asymmetric Cell Division and Notch Signaling Specify Dopaminergic Neurons in Drosophila

Murni Tio,Gerald Udolph,Wanru Fang,Joanne Toh,Jorge Blanco,Edward Giniger

doi:10.1371/journal.pone.0026879

Murni Tio, Gerald Udolph + Show 4 more

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https://doi.org/10.1371/journal.pone.0026879

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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.

Highlights

Asymmetric cell division (ACD) is a fundamental mechanism generating cell fate diversity during nervous system development [1,2]
Tyrosine Hydroxylase (TH) protein expression was first observed at stage 14 (St14) in one neuron per segment in the ventral midline representing the H-cell [23]
While quite recently the roles of asymmetric cell division (ACD) and Notch signaling have been demonstarted for the specification of the ventral midline derived H-cell, not much is known about the mechanisms of specification for the majority of DA neurons which are derived from the lateral and procephalic neuroectoderm

Summary

Introduction

Asymmetric cell division (ACD) is a fundamental mechanism generating cell fate diversity during nervous system development [1,2]. NBs localize proteins such as Inscuteable (Insc) [5] and Bazooka (Baz) [6,7] to the apical cortex and proteins such as Numb [8,9] and Partner of Numb (Pon) [10] to the basal cortex. Pon physically interacts with Numb and directs asymmetric localization of Numb [10]. The apical proteins or protein complexes control the localization of the basal proteins [2]. GMC division is asymmetric and results in two siblings with distinct cell fates [11]

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