Abstract

The Notch gene encodes an evolutionarily conserved cell surface receptor that generates regulatory signals based on interactions between neighboring cells. In Drosophila embryos it is normally expressed at a low level due to strong negative regulation. When this negative regulation is abrogated neurogenesis in the ventral region is suppressed, the development of lateral epidermis is severely disrupted, and the dorsal aminoserosa is expanded. Of these phenotypes only the anti-neurogenic phenotype could be linked to excess canonical Notch signaling. The other phenotypes were linked to high levels of Notch protein expression at the surface of cells in the lateral regions indicating that a non-canonical Notch signaling activity normally functions in these regions. Results of our studies reported here provide evidence. They show that Notch activities are inextricably linked to that of Pkc98E, the homolog of mammalian PKCδ. Notch and Pkc98E up-regulate the levels of the phosphorylated form of IκBCactus, a negative regulator of Toll signaling, and Mothers against dpp (MAD), an effector of Dpp signaling. Our data suggest that in the lateral regions of the Drosophila embryos Notch activity, in conjunction with Pkc98E activity, is used to form the slopes of the opposing gradients of Toll and Dpp signaling that specify cell fates along the dorso-ventral axis.

Highlights

  • Developmental function of Notch was discovered in Drosophila embryos more than 70 years ago [1]

  • When Notch expressed on one proneural cell binds its ligand Delta expressed on a neighboring proneural cell, Notch is first cleaved in the extracellular region by the Kuzbanian/ ADAM 10 protease and subsequently in the transmembrane region by the Presenilin/c-Sectretase protease complex to release the Notch intracellular domain (Nintra/NICD)

  • Canonical Notch signaling is activated in the remaining cells of proneural clusters, which commit to the alternate epidermal fate by expressing epidermal genes of the Enhancer of split Complex (E(spl)C, HES) [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27]

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Summary

Introduction

Developmental function of Notch was discovered in Drosophila embryos more than 70 years ago [1]. Nintra/NICD translocates to the nucleus and in association with the DNA binding protein Suppressor of Hairless (RBP-Jk) promotes transcription of target genes. This signaling (referred to as canonical Notch signaling) is blocked in a few cells within each proneural cluster, which commit to the neuronal fate by expressing neuronal genes (e.g., hunchback) and differentiate the CNS. Canonical Notch signaling is activated in the remaining cells of proneural clusters, which commit to the alternate epidermal fate by expressing epidermal genes of the Enhancer of split Complex (E(spl)C, HES) [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27]

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