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Astrocyte Development and Function Is Fgf8 Signaling

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Astrocyte Development and Function Is Fgf8 Signaling ASTROCYTE DEVELOPMENT AND FUNCTION IS FGF8 SIGNALING DEPENDENT A dissertation submitted to Kent State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy by Courtney E. Stewart May 2019 © Copyright All Rights Reserved Except for previously published materials Dissertation written by Courtney E. Stewart B.S., Kent State University 2013 Ph.D., Kent State University 2019 Approved by ___________________________________, Chair, Doctoral Dissertation Committee Wilson C.J. Chung Ph.D. ___________________________________, Members, Doctoral Dissertation Committee Jennifer A. McDonough Ph.D. ___________________________________, Samuel D. Crish Ph.D. ___________________________________, Kristy Welshhans Ph.D. ___________________________________, Mary Beth Spitznagel Ph.D. Accepted by ___________________________________, Chair, Department of Biomedical Sciences Ernest J. Freeman Ph.D. ___________________________________, Dean, College of Arts and Sciences James L. Blank Ph.D. Table of Contents Table of Contents .....………………………………………...………………………………….. iii List of Figures ….........………………………………………………………………………….. vi List of Tables …………........…………………………………………….....…………………. viii List of Abbreviations ……….............………………………………………….………………... x Acknowledgments ....………………............…………………………………………………... xii Chapter 1: General Introduction ….......................………………………......………………...... 1 1.1. Fibroblast growth factor signaling in brain development ....................................................... 1 1.2. FGF8 signaling in astrocyte development .............................................................................. 4 1.3. FGF8 signaling in astrocyte function and astrocyte specific diseases .................................... 7 1.4. FGF8 signaling in astrocyte function .................................................................................... 10 1.5. Models of astrocyte activation within MS ............................................................................ 12 1.6. Specific aims ......................................................................................................................... 16 1.7. References ............................................................................................................................. 19 Chapter 2: Perinatal Midline Astrocyte Development is Impaired in Fibroblast Growth Factor 8 Hypomorphic Mice ...................................................................................................................... 30 2.1. Introduction ........................................................................................................................... 30 2.2. Materials and Methods .......................................................................................................... 33 2.3. Results ................................................................................................................................... 40 2.4. Discussion ............................................................................................................................. 55 2.5. References ............................................................................................................................. 61 iii 2.6 Supplementary information ................................................................................................... 65 Chapter 3: Perinatal FGF8 Hypomorphic Mouse Anterior Midline Glial Cell Development is Independent of Genetic Sex ......................................................................................................... 66 3.1. Introduction ........................................................................................................................... 66 3.2. Materials and Methods .......................................................................................................... 69 3.3. Results ................................................................................................................................... 72 3.4. Discussion ............................................................................................................................. 79 3.5. References ............................................................................................................................. 82 Chapter 4: Cuprizone Induced Mouse Astrocyte Activation is Fibroblast Growth Factor 8 Signaling-dependent .................................................................................................................... 86 4.1. Introduction ........................................................................................................................... 86 4.2. Material and Methods ........................................................................................................... 89 4.3. Results ................................................................................................................................... 93 4.4. Discussion ........................................................................................................................... 106 4.5. References ........................................................................................................................... 110 Chapter 5: Analyzing Cuprizone Effects on Corpus Callosum Thickness with Magnetic Resonance Imaging in the Adult Mouse Brain .......................................................................... 113 5.1. Introduction ......................................................................................................................... 113 5.2. Material and Methods ......................................................................................................... 115 5.3. Results ................................................................................................................................. 118 iv 5.4. Discussion ........................................................................................................................... 122 5.5. References ........................................................................................................................... 125 Chapter 6: General Discussion ................................................................................................. 128 6.1. FGF8 regulates astrocyte development during CC formation ............................................ 129 6.2. FGF8 is of importance during astrocyte activation when challenged with the neurotoxin cuprizone .................................................................................................................................... 131 6.3. The cellular signaling mechanisms underlying FGF8-dependent astrocyte development and function ...................................................................................................................................... 135 6.4. Future directions ................................................................................................................. 136 6.5. Conclusions ......................................................................................................................... 138 6.6. References ........................................................................................................................... 139 v List of Figures Figure 2.1. GAP43 immunoreactivity in anterior-dorsal midline region in PN0 WT, Fgf8+/neo , and Fgf8neo/neo hypomorphic mice ................................................................................................ 41 Figure 2.2. NP-1 immunoreactivity in anterior-dorsal midline region in E16.5 and PN0 WT, Fgf8+/neo , and Fgf8neo/neo hypomorphic mice ............................................................................... 43 Figure 2.3. Incidence of apoptosis within the anterior-dorsal midline region in E16.5 and E17.5 WT, Fgf8+/neo , and Fgf8neo/neo hypomorphic mice ....................................................................... 45 Figure 2.4. S100b immunoreactivity within the anterior-dorsal midline region in E17.5 and PN0 WT, Fgf8+/neo , and Fgf8neo/neo hypomorphic mice ....................................................................... 47 Figure 2.5. GFAP immunoreactivity within the anterior-dorsal midline region in E17.5 and PN0 WT, Fgf8+/neo , and Fgf8neo/neo hypomorphic mice ....................................................................... 51 Figure 2.6. GFAP immunoreactivity within the anterior-dorsal midline region in adult WT and Fgf8+/neo hypomorphic mice ......................................................................................................... 54 Figure 2.7. GLAST-1 immunoreactivity within the anterior-dorsal midline region in PN0 WT, Fgf8+/neo , and Fgf8neo/neo hypomorphic mice ............................................................................... 65 Figure 3.1. GFAP immunoreactivity within the anterior-dorsal midline in male and female E17.5 WT, Fgf8+/neo , and Fgf8neo/neo hypomorphic mice ....................................................................... 73 Figure 3.2. GFAP immunoreactivity within the anterior-dorsal midline in male and female PN0 WT, Fgf8+/neo , and Fgf8neo/neo hypomorphic mice ....................................................................... 75 Figure 3.3. GFAP immunoreactivity within the anterior-dorsal midline in male and female PN5 WT, Fgf8+/neo , and Fgf8neo/neo hypomorphic mice ....................................................................... 77 vi
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