Recent studies have documented important roles for heparan sulfate proteoglycans (HSPGs) in aging and development of the nervous system. HSPGs are proposed to regulate processes as diverse as neural cell differentiation, cell adhesion, and the pathogenesis of human diseases such as Alzheimer's disease (AD). Recent studies from our laboratories have shown that agrin is a major extracellular matrix (ECM) and transmembrane HSPG in nervous tissue. Agrin is an extracellular matrix protein identified and named based on its involvement in the aggregation of acetylcholine receptors (AChRs) during synaptogenesis at the neuromuscular junction (NMJ). Emerging evidence indicates that agrin's function is not limited to its role in synaptogenesis, as agrin modulates axon extension, is expressed in adult brain, and may contribute to the etiology of some neurodegenerative diseases. The studies outlined in this proposal are aimed at understanding mechanisms by which agrin functions in brain development and aging. The specific goals of this proposal are: 1) To analyze the role of agrin in neurogenesis, neural patterning and axonal growth in the developing CMS, using in vivo approaches in chicken and zebrafish embryos. These studies will focus on analyzing the role agrin plays in modulating the function of heparin-binding signaling molecules such as the fibroblast growth factors (FGFs). Agrin morpholino oligonucleotides will be employed to knock-down agrin expression during chick or zebrafish development, and will be combined with inhibitors of FGF receptor function or FGF overexpression to explore agrin's role in the modulation of FGF signaling during development. 2) To elucidate the molecular mechanisms by which agrin regulates posterior development in zebrafish. These studies will test the hypothesis that agrin, via regulation of FGF signaling pathways, is necessary for posterior development in zebrafish. 3) To examine the role of agrin in the regulation of beta-amyloid aggregation, clearance and cytotoxicity in AD brain. These studies represent a continuation of our studies that suggest a crucial role for agrin in modulating beta-amyloid aggregation. These studies will include the use of AD mouse models to investigate further the role of agrin in AD. We predict that these proposed studies will provide important new insight into the function of agrin in the developing and aging nervous system. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurodegeneration and Biology of Glia Study Section (NDBG)
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Tagle, Danilo A
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North Carolina Central University
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Hu, Bo; Chen, Hao; Liu, Xiuping et al. (2013) Transgenic overexpression of cdx1b induces metaplastic changes of gene expression in zebrafish esophageal squamous epithelium. Zebrafish 10:218-27
Zhang, Chengjin; Turton, Qwan M; Mackinnon, Shanta et al. (2011) Agrin function associated with ocular development is a target of ethanol exposure in embryonic zebrafish. Birth Defects Res A Clin Mol Teratol 91:129-41
Hu, Bo; Zhang, Chengjin; Baawo, Kouwendy et al. (2010) Zebrafish K5 promoter driven GFP expression as a transgenic system for oral research. Oral Oncol 46:31-7
Liu, I-Hsuan; Zhang, Chengjin; Kim, Min Jung et al. (2008) Retina development in zebrafish requires the heparan sulfate proteoglycan agrin. Dev Neurobiol 68:877-98
Lee, Ju-Ahng; Anholt, Robert R H; Cole, Gregory J (2008) Olfactomedin-2 mediates development of the anterior central nervous system and head structures in zebrafish. Mech Dev 125:167-81
Lee, Ju-Ahng; Cole, Gregory J (2007) Generation of transgenic zebrafish expressing green fluorescent protein under control of zebrafish amyloid precursor protein gene regulatory elements. Zebrafish 4:277-86
Kim, Min Jung; Liu, I-Hsuan; Song, Yuanquan et al. (2007) Agrin is required for posterior development and motor axon outgrowth and branching in embryonic zebrafish. Glycobiology 17:231-47
Wakamatsu, Yoshio; Nakamura, Noriko; Lee, Ju-Ahng et al. (2007) Transitin, a nestin-like intermediate filament protein, mediates cortical localization and the lateral transport of Numb in mitotic avian neuroepithelial cells. Development 134:2425-33
Liu, I-Hsuan; Uversky, Vladimir N; Munishkina, Larissa A et al. (2005) Agrin binds alpha-synuclein and modulates alpha-synuclein fibrillation. Glycobiology 15:1320-31
Hummel, Susanna; Osanger, Andreas; Bajari, Tarek M et al. (2004) Extracellular matrices of the avian ovarian follicle. Molecular characterization of chicken perlecan. J Biol Chem 279:23486-94

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