Nucleocytoplasmic Transport Regulation
In eukaryotic cells, transcription and translation processes are physically separated by the nuclear envelope (NE). Thus, the proper functions of a cell involve nuclear mRNA export for protein synthesis in the cytoplasm and protein nuclear transport across the NE (Figure 1A). Defective nucleocytoplasmic transport (NCT) has emerged as a common molecular underpinning of many neurological diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). The systematic analyzation of the regulation of NCT will provide novel insights into the nuclear transport machinery and advance our understanding of how defective NCT contributes to human diseases. We use electron microscopy (EM) to examine the ultrastructure of cells, including the nuclear envelope and nuclear pore complex (NPC) (Figure 1B). We have established two systems to analyze nuclear transport function in cultured mammalian cells. One approach measures nuclear mRNA export using fluorescent in situ hybridization (FISH) with oligo-dT probes combined with immuno-staining of NE markers (Figure 1C). Another approach analyzes protein nuclear transport using lentiviral delivery of a dual reporter expressing GFP-NES and RFP-NLS (Figure 1D). Research efforts are focused on molecular mechanisms of NCT machinery and identification of dysregulated factors that disrupt NCT in aging and diseased cells.
Ding B*, Tang Y, Ma S, Akter M, Liu ML, Zang T, Zhang CL.(2021). Disease modeling with human neurons reveals LMNB1 dysregulation underlying DYT1 dystonia. J Neurosci. 2021 Jan 15:JN-RM-2507-20. DOI: 10.1523/JNEUROSCI.2507-20.2020. PMID: 33468570
Ding B, Akter M and Zhang C-L. (2020). Differential Influence of Sample Sex and Neuronal Maturation on mRNA and Protein Transport in Induced Human Neurons. Front. Mol. Neurosci. 13:46.
Ding B., Mirza A,M., Alshley J. Budnik V. and Munson M. (2017) Nuclear Export Through Nuclear Envelope Remodeling in Saccharomyces cerevisiae. bioRxiv (Priprint) PDF
Li Y, Hassinger L, Thomson T, Ding B, Ashley J, Hassinger W and Budnik V. (2016). Lamin Mutations Accelerate Aging via Defective Export of Mitochondrial mRNAs through Nuclear Envelope Budding. Curr Biol. 2016 Aug 8;26(15):2052-9 PDF
Packard M, Jokhi V, Ding B and Budnik V. (2015) Nucleus to Synapse Nesprin Railroad Tracks Direct Synapse Maturation through RNA localization. Neuron. 86(4):1015-28) PDF