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Investigation of Common Bases of Sympathetic Nervous System and Neuroblastoma Development

Shi, Huilin
http://rave.ohiolink.edu/etdc/view?acc_num=mco1244058100

Abstract Details

2009, Doctor of Philosophy in Biomedical Sciences (Ph.D.), University of Toledo, College of Medicine.
Sympathetic ganglia are primarily composed of noradrenergic neurons andsatellite glial cells. Although both cell types originate from neural crest cells, the identities of the progenitor populations at intermediate stages of the differentiation process remain to be established. Here we report the identification in vivo of glial and neuronal progenitor cells in postnatal sympathetic ganglia, using mouse superior cervical ganglia as a model system. There are significant levels of cellular proliferation in mouse superior cervical ganglia during the first 18 days after birth. A majority of the proliferating cells express both nestin and brain lipid-binding protein (BLBP). BrdU fate-tracing experiments demonstrate that these nestin and BLBP double positive cells represent a population of glial progenitors for sympathetic satellite cells. The glial differentiation process is characterized by a marked downregulation of nestin and upregulation of S100, with no significant changes in the levels of BLBP expression. We also identify a small number of proliferating cells that express nestin and tyrosine hydroxylase, a key enzyme of catecholamine biosynthesis that defines sympathetic noradrenergic neurons. Together, these results establish nestin as a common marker for sympathetic neuronal and glial progenitor cells and delineate the cellular basis for the generation and maturation of sympathetic satellite cells. This research in the normal postnatal sympathetic development provides the basis for the neuroblastoma study. Neuroblastoma is the most common childhood malignant tumor which originates from sympathetic nervous system. 90% of children with this disease are diagnosed before 6 years old. Therefore, the tumorigenesis of neuroblastoma may represent an abnormal embryonic or postnatal sympathetic development. Transformed neural crest stem cells or malignant sympathetic precursor cells that obtain stem cell abilities are recognized as neuroblastoma stem cells that might be the origin of neuroblastoma. BE(2)-C cells, a human neuroblastoma cell line enriched with tumorigenic stem cells, can be induced to undergo either neuronal or glial differentiation. We use BE(2)-C cells as a system to identify the genes that regulate neuroblastoma stem cell activities, such as self-renewal and differentiation. One of these genes is GATA3, a zinc-finger transcription factor with an essential role in sympathetic development. Downregulation of GATA3 by siRNA promotes BE(2)- C cell proliferation and overexpression of GATA3 decreases the proliferation of BE(2)-C cells. GATA3 regulates cell proliferation through distinct pathways involving Cyclin D1 and E2F1, as evidenced by an increased expression of Cyclin D1 and a decreased expression of E2F1 in GATA3 knockdown cells. In addition, GATA3 knockdown induces BE(2)-C cells to undergo glial differentiation, as indicated by an increase in the expression of GFAP, a glial cell marker, and a decrease in the expression of neuronal marker SNAP25. GATA3 overexpression promotes neuronal differentiation of BE(2)-C cells, as indicated by a reduction of GFAP expression and an upregulation of SNAP25 expression. GATA3 knockdown also downregulates Phox2b and GATA3 overexpression upregulates Mash1, two transcription factors that are expressed in neuronal progenitor cells and are essential for sympathetic development. Together, these findings suggest that GATA3, Phox2b and Mash1 may function in a regulatory network in the control of neuroblastoma cells in a stem/progenitor cell state.
Han-Fei Ding, Ph.D. (Committee Chair)
William Maltese, Ph.D. (Committee Member)
Manohar Ratnam, Ph.D. (Committee Member)
Ivana de la Serna, Ph.D. (Committee Member)
Zi-Jian Xie, Ph.D. (Committee Member)
Hongjuan Cui, Ph.D. (Committee Member)
199 p.
Biology; Molecular Biology; Neurology; Oncology
neuroblastoma; sympathetic development; cancer stem cell; GATA3; nestin

Recommended Citations

Citations

  • Shi, H. (2009). Investigation of Common Bases of Sympathetic Nervous System and Neuroblastoma Development [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1244058100

    APA Style (7th edition)

  • Shi, Huilin. Investigation of Common Bases of Sympathetic Nervous System and Neuroblastoma Development. 2009. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1244058100.

    MLA Style (8th edition)

  • Shi, Huilin. "Investigation of Common Bases of Sympathetic Nervous System and Neuroblastoma Development." Doctoral dissertation, University of Toledo, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=mco1244058100

    Chicago Manual of Style (17th edition)

mco1244058100
617
© 2009, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.