SAGA-mediated H2B deubiquitination controls the development of neuronal connectivity in the Drosophila visual system

Abstract

Nonstop, which has previously been shown to have homology to ubiquitin proteases, is required for proper termination of axons R1–R6 in the optic lobe of the developing Drosophila eye. Herein, we establish that Nonstop actually functions as an ubiquitin protease to control the levels of ubiquitinated histone H2B in flies. We further establish that Nonstop is the functional homolog of yeast Ubp8, and can substitute for Ubp8 function in yeast cells. In yeast, Ubp8 activity requires Sgf11. We show that in Drosophila, loss of Sgf11 function causes similar photoreceptor axon‐targeting defects as loss of Nonstop. Ubp8 and Sgf11 are components of the yeast SAGA complex, suggesting that Nonstop function might be mediated through the Drosophila SAGA complex. Indeed, we find that Nonstop does associate with SAGA components in flies, and mutants in other SAGA subunits display nonstop phenotypes, indicating that SAGA complex is required for accurate axon guidance in the optic lobe. Candidate genes regulated by SAGA that may be required for correct axon targeting were identified by microarray analysis of gene expression in SAGA mutants.

TAF10 and TAF10b partially redundant roles duringDrosophila melanogastermorphogenesis

“…Loss of the dSAGA subunits resulted in photoreceptor axon-targeting defects indicating that the dTAF10 containing dSAGA complex plays a role in neuronal development in the optic lobe. 32 We also show that dTaf10 silencing results in increased apoptosis and wing morphology abnormalities.…”

Flickin’ the ubiquitin switch

“…Ubp8 and Ubp10 are the yeast homologues of Nonstop and Scny respectively ( Table 1). 29,33 Global levels of H2Bub1 are increased to a greater extent in mutants deficient for both enzymes than either one alone, indicating non-overlapping targets of these proteases. 11,23 This is reflected in their distinct functional roles, and patterns of localization; Ubp10 is preferentially localized to silenced regions of the genome, while Ubp8 shows no such preference.…”

“…34,35 Nonstop is the fly orthologue of yeast Ubp8, a component of the SAGA complex required for the activation of certain stressinducible genes (Table 1). 10,33 Weake et al 33 demonstrated that Nonstop may affect glial migration as part of the SAGA complex, as mutations in genes encoding other components of SAGA also disrupt axonal projections to varying extents. 33 Of considerable interest is the finding that reducing the deubiquitylation activity of SAGA in muscle results in a preferential downregulation of genes required specifically for muscle development.…”

“…Further to the requirement for Scny, a second H2B ubiquitin protease, Nonstop, also plays a role in fruit fly development. [33][34][35] First identified as the result of a screen for mutations that affect neuronal connectivity in the brain, Nonstop expression in glia was subsequently found to be required for the migration of these cells into the axonal projection field. 34,35 Nonstop is the fly orthologue of yeast Ubp8, a component of the SAGA complex required for the activation of certain stressinducible genes (Table 1).…”

Drosophila models reveal novel insights into mechanisms underlying neurodegeneration

“…8 Increasingly, however, evidence has indicated that regulation of SAGA in multicellular organisms involves more sophisticated mechanisms than in their unicellular counterparts. 9,10 In order to gain more insight into SAGA function in multicellular eukaryotes, we turned to Drosophila. This model provided powerful genetic and biochemical tools in which to explore principles underlying SAGA-mediated gene regulation.…”