Vitamin D3 up-regulated protein 1 (VDUP1) contributes to neural fate specification during Drosophila brain development.
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Issue Date
2014
Authors
Khanna, Payal '14
Degree
MS in Pharmaceutical Sciences
Advisor
Dearborn, Richard
Committee Members
Voigt, Jeffrey M.
Malik, Meenakshi
Malik, Meenakshi
Journal Title
Journal ISSN
Volume Title
Abstract
The proliferation and differentiation of neural stem cells regulates brain growth in many organisms, including Drosophila melanogaster. In Drosophila, these neural stem cells, or neuroblasts (NB), have emerged as an important model system for studying both stem cell biology as well as mechanisms underlying brain tumorigenesis. NBs divide asymmetrically to produce two daughter cells, one of which retains NB identity and the other which continues to divide and differentiate to generate the neurons and glia of the central nervous system (CNS). Mutations in genes that control NB division processes result in the production of excess, undifferentiated, self-renewing cells that mimic tumor cells, suggesting shared underlying circuitry. Thus, the identification and characterization of genes involved in the regulation of NB proliferation and differentiation is critical to understanding both normal and pathological brain growth. Recently, vitamin D3 up-regulated protein 1 (VDUP1), also known as thioredoxin interacting protein (TxNIP), has emerged as a novel candidate gene within this NB circuitry. VDUP1 is expressed in dynamic patterns within cells of the Drosophila central nervous system (CNS), including NBs, at all stages of development. Specifically, the down-regulation of VDUP1 within NBs appeared to coincide with NB division processes leading to the hypothesis that VDUP1 might be involved in the regulation of NB proliferation and/or progeny differentiation, controlling subsequent brain growth. Indeed, RNAi-mediated knock-down of VDUP1 expression within the developing brain resulted in marked reduction of neural differentiation markers within NB progeny cells, identifying a novel role for VDUP1 in the regulation of neurogenesis. Knock-down of VDUP1 was further correlated with an increase in progeny cell size and decreased expression of cyclin-A, which is required for cell progression through G2. Over-expression of VDUP1--triggered genetically or metabolically by increased glucose consumption--resulted in delayed development, smaller brains and abnormal brain morphology including diminished NB and progeny cell sizes. Taken together these data suggest that VDUP1 may function to control cell growth and differentiation within the developing CNS. Importantly, VDUP1 knock-down phenotypes persisted into adult stages--characterization of these phenotypes may ultimately generate a new model for the study of brain tumorigenesis.
Citation
Khanna P. Vitamin D3 up-regulated protein 1 (VDUP1) contributes to neural fate specification during drosophila brain development [thesis]. Ann Arbor (MI): Proquest LLC; 2014. 75 p.
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