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Astrocyte Development and Function is FGF8 Signaling Dependent

Stewart, Courtney Elizabeth
http://orcid.org/0000-0003-0641-6827
http://rave.ohiolink.edu/etdc/view?acc_num=kent1556290142104336

Abstract Details

2019, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
Brain development is dependent upon multiple ligand/receptor combinations within fibroblast growth factor (FGF) / fibroblast growth factor receptor (FGFR) signaling. FGFs are crucial for brain development as they regulate cell proliferation, specification, differentiation, migration and survival. Most FGF ligand actions during brain development are region-specific and many knockout studies have shown FGFs are involved in neural induction, brain symmetry, cortical, forebrain, midbrain and cerebellar development. Here, we showed that FGF8 signaling, which is known to provide trophic support for astrocytes during development, is also required for proper midline astrocyte development and function. Specifically, we showed that a Fgf8 deficit delayed the acquisition of GFAP ultimately impairing the maturation of midline astrocytes, and subsequently resulting in agenesis of the corpus callosum (ACC). To our surprise, this delay in astrocyte maturation was transient, as adult Fgf8 hypomorphic mice expressed midline astrocytic GFAP levels identical to their WT littermates indicating that astrocyte development in mice with FGF8 deficits normalized in adulthood. However, this did not rule out the possibility that perinatal Fgf8 deficits may have permanent effects on astrocyte function, such as astrocyte activation. Therefore, we stressed Fgf8 hypomorphic astrocytes with cuprizone (CPZ), a toxin which can target and activate corpus callosum specific astrocytes, and compared the astrocyte activation response between WT and Fgf8+/neo hypomorphic mice. We found that a perinatal Fgf8 deficit permanently impaired midline astrocytic function. Specifically, astrocytes within the cingulum region of the corpus callosum in adult Fgf8+/neo CPZ-fed hypomorphic mice exhibited a delay in GFAP acquisition, and an altered astrocytic branching morphology. Furthermore, callosal cell populations within Fgf8+/neo CPZ-fed hypomorphic mice exhibited an abnormal second messenger system profile when compared to WT CPZ-fed mice. Specifically, Fgfr1 and Stat3 mRNA increased in CPZ-fed Fgf8+/neo hypomorphic mice. These studies demonstrate that, in addition to FGF8’s role as a source of astrocytic trophic support, FGF8 also plays an important role in GFAP acquisition, astrocyte maturation and astrocyte activation. Together, these studies have expanded our knowledge on, not only FGF8’s role in brain development, but also how FGF8 regulates astrocyte development and function.
Wilson Chung, Ph.D. (Advisor)
Jennifer McDonough , Ph.D. (Committee Member)
Samuel Crish, Ph.D. (Committee Member)
Kristy Welshhans, Ph.D. (Committee Member)
Mary Beth Spitznagel, Ph.D. (Committee Member)
142 p.
Biomedical Research; Neurosciences
FGF8; Astrocytes; GFAP; Astrocyte Activation; Agenesis of the corpus callosum

Recommended Citations

Citations

  • Stewart, C. E. (2019). Astrocyte Development and Function is FGF8 Signaling Dependent [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1556290142104336

    APA Style (7th edition)

  • Stewart, Courtney. Astrocyte Development and Function is FGF8 Signaling Dependent . 2019. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1556290142104336.

    MLA Style (8th edition)

  • Stewart, Courtney. "Astrocyte Development and Function is FGF8 Signaling Dependent ." Doctoral dissertation, Kent State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=kent1556290142104336

    Chicago Manual of Style (17th edition)

kent1556290142104336
422
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This open access ETD is published by Kent State University and OhioLINK.