School of Biology and BME Seminar

Anita H Corbett, PhD Emory University, Dept of Biochemistry, Dept of Cell Biology

Abstract:

We have recently identified the first gene encoding a polyadenosine RNA binding protein, ZC3H14 (Zinc finger CysCysCysHis domain-containing protein 14), which is mutated in inherited, nonsyndromic, autosomal recessive intellectual disability. This finding uncovers the molecular basis for disease in these patients and provides strong evidence that ZC3H14 is essential for proper brain function. ZC3H14 is an evolutionarily conserved member of a novel class of tandem zinc finger (CCCH) polyadenosine RNA-binding proteins. Our studies of ZC3H14 orthologs in a Drosophila model provide evidence that the function of ZC3H14 is critical for proper neuronal function as well as overall brain morphology. To understand the function of ZC3H14 in the vertebrate brain, we have initiated studies in mice. Analysis of the localization of the Zc3h14 protein in mouse primary hippocampal neuronal cultures reveals that Zc3h14 is localized to nuclear speckles but also found in the cytoplasm with enrichment in axons. This new finding positions cytoplasmic Zc3h14 in the context of regulating post-transcriptional RNA processing outside the nucleus, suggesting possible roles in modulating transport, turnover, and/or local translation of target RNA. To further assess the function of vertebrate ZC3H14, we have generated a Zc3h14 knockout mouse. We have performed both proteomic and RNA-Seq analysis comparing wildtype and knockout mouse hippocampi to reveal dysregulated pathways and identify potential Zc3h14 target transcripts. The proteomic studies identify several GO-term pathways including synapse, cell projection, and transmission of nerve impulse, which are dysregulated in the knockout hippocampus. In contrast, RNA-Seq analysis reveals that the steady-state levels of mRNAs are not significantly altered in control compared to knockout hippocampi consistent with a critical role for ZC3H14 in post-transcriptional regulation through RNA localization or translational control. We suggest a model where ZC3H14 cooperates with multiple complexes in the nucleus to ensure proper mRNA processing but then also has the potential to function in the cytoplasm to modulate local translation of target transcripts.