Abstract
The human ZC3H14 gene, which encodes a ubiquitously expressed polyadenosine zinc finger RNA-binding protein, is mutated in an inherited form of autosomal recessive, nonsyndromic intellectual disability. To gain insight into neurological functions of ZC3H14, we previously developed a Drosophila melanogaster model of ZC3H14 loss by deleting the fly ortholog, Nab2. Studies in this invertebrate model revealed that Nab2 controls final patterns of neuron projection within fully developed adult brains, but the role of Nab2 during development of the Drosophila brain is not known. Here, we identify roles for Nab2 in controlling the dynamic growth of axons in the developing brain mushroom bodies, which support olfactory learning and memory, and regulating abundance of a small fraction of the total brain proteome. The group of Nab2-regulated brain proteins, identified by quantitative proteomic analysis, includes the microtubule-binding protein Futsch, the neuronal Ig-family transmembrane protein turtle, the glial:neuron adhesion protein contactin, the Rac GTPase-activating protein tumbleweed, and the planar cell polarity factor Van Gogh, which collectively link Nab2 to the processes of brain morphogenesis, neuroblast proliferation, circadian sleep/wake cycles, and synaptic development. Overall, these data indicate that Nab2 controls the abundance of a subset of brain proteins during the active process of wiring the pupal brain mushroom body and thus provide a window into potentially conserved functions of the Nab2/ZC3H14 RNA-binding proteins in neurodevelopment.
Highlights
Guidance is regulated in part by local translation of mRNAs within the growth cone that modifies the local proteome
This process of local translation, which relies on predelivery of mRNAs to the axon tip, facilitates rapid shifts in translation in response to extracellular cues that would otherwise be limited by distance from the nucleus and relatively slow speed of intracellular transport [1,2,3,4]
RNA-binding proteins (RBPs) play broadly important roles in regulating multiple steps in gene expression shared by all cell types, mutations in genes encoding RBPs often result in tissue type– or cell type–specific diseases [2, 4, 6,7,8,9,10]
Summary
Our prior finding that loss of Nab impairs MB neuromorphology in the mature adult Drosophila brain [4, 6, 7] suggests a role for Nab in MB morphogenesis in the preceding pupal phase. Gene ontology (GO) analysis for biological process enrichment was performed with FlyEnrichr by analyzing the differentially expressed (Nab2ex versus control and Nab oe versus control) protein datasets. The 152 proteins that are significantly changed only in Nab2ex brains, and not in the Nab oe genotype (which is in the Nab2ex background), are rescued by re-expression of WT Nab in Nab2ex brain neurons These differences in Nab2ex and Nab oe differentially expressed proteins are reflected in the FlyEnrichr GO analysis, which reveals 172 terms unique to Nab2ex and 999 unique to Nab oe (Fig. 4C). Factors that decrease in protein abundance, whether due to direct or indirect effects of Nab, may be phenotypically significant in the Nab2ex genotype To parse these effects, the unique and shared changes in the Nab2ex3-DE and Nab2oe-DE datasets were further divided into increased and decreased groups, and subjected to FlyEnrichr analysis (Fig. 4C). Kinase anchor protein 200, the condensin subunit gluon, and the neuroblast regulator Polo (Fig. 5D)
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