A broad underlying cause of human disease is the incorrect spatial or temporal control of gene expression. The nuclear pore complex (NPC), which was long regarded simply as a gateway through which molecules move in and out of the nucleus, has emerged as an important modulator of expression. A novel link between the NPC and developmental signaling pathways, another key regulator of gene transcription, has been discovered in Drosophila, which motivates the proposed research. Megator, the fly homolog of the Tpr nuclear pore protein, was identified as a binding partner for the Wg/Wnt inhibitor, Tum. Loss of Megator function in the developing fly wing disrupted expression of Wg target genes without disrupting production of Wg itself, indicating that Megator is required for proper response to Wg/Wnt signaling. Two other nucleoporins (Nups) that were identified subsequently also appear to regulate developmental pathways. Loss of Nup154/155 or Nup214 function drastically disrupted the developing wing and leg without affecting other developing tissues. The unique pattern defects caused by Megator, Nup 154/155 or Nup214 disruption suggest that they are involved in cellular processes beyond just structural integrity of the NPC. They may target the nuclear import of key signaling pathway components, modulate signaling pathways independently of the NPC, or organize chromatin within the nucleus in ways that differentially influence the target genes of specific signaling pathways. The goal of this project is to distinguish among these hypotheses for the tissue-specific nature of the Nup activities, using the powerful molecular and genetic tools available in the Drosophila model system. Cell to cell signaling is required for embryonic patterning in all animals. In humans, loss of proper signaling leads to birth defects, whereas hyperactivity of some developmental pathways is associated with a variety of childhood and adult cancers. Because signaling pathways in Drosophila are highly conserved with humans, what is learned in the fly will be directly applicable to human cell biology. By studying these pathways and their interaction with the NPC, this project aims to provide new insight into disparate human disease states, and may reveal that they share similar cellular underpinnings. The results obtained in these exploratory experiments will guide future investigation into the relationship between signal transduction and the NPC. This work has the potential to blaze a new trail in understanding how nuclear architecture influences normal development and disease processes.

Public Health Relevance

Defects in nucleus structure are associated with a variety of human diseases, ranging from progeria (accelerated aging) to muscular dystrophy. We have discovered a novel link between nuclear structure and cell signaling pathways; understanding this link will lead to develop better therapies for diseases associated with nucleus pathology.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Intercellular Interactions Study Section (ICI)
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Mukhopadhyay, Mahua
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Duke University
Schools of Arts and Sciences
United States
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