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Open Dissertation Edited Final 11 The Pennsylvania State University The Graduate School Intercollege Graduate Program in Neuroscience RBM8A IS REQUIRED FOR NORMAL CORTICAL DEVELOPMENT A Dissertation in Neuroscience by Colleen McSweeney 2017 Colleen McSweeney Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy December 2017 ii The dissertation of Colleen McSweeney was reviewed and approved* by the following: Yingwei Mao Associate Professor of Biology Dissertation Advisor Chair of Committee David Vandenbergh Professor of Biobehavioral Health Bernhard Lüscher Professor of Biology, Biochemistry, and Molecular Biology Gong Chen Professor of Biology Verne M. Willaman Chair in Life Sciences Kevin Alloway Professor of Neural and Behavioral Sciences Program Chair *Signatures are on file in the Graduate School iii ABSTRACT The formation of the nervous system requires a balance between proliferation, differentiation and migration of neural progenitors, resulting in a neural network that mediates both behaviors and autonomic functions. Here, we identified an exon junction complex protein , RBM8a, as a positive regulator of embryonic neural progenitor cell proliferation and differentiation. We determined that RBM8a knockdown (using in utero electroporation) leads to increased migration of neural progenitor cells (NPCs) to the cortical plate (CP), depletion of the NPC pool, and a decrease in the number of cells in the DNA synthesis phase of the cell cycle. Conversely, RBM8a overexpression leads to decreased migration of NPCs to the CP, expansion of the progenitor pool, and increased proliferation. In order to further explore the role of RBM8a in neurogenesis, we developed a conditional knockout mouse. We selectively knocked out RBM8a in neural stem cells, and the resulting mice exhibited microcephaly, early postnatal lethality, and altered distribution of neurons in the neocortex. We then assessed the novel role of RBM8a in the development of GABAergic interneurons in the cortex. We discovered that in addition to the profound phenotypes observed in mice with reduced expression of RBM8a in excitatory neurons previously described in (Mao et al., 2015), Nes-cre;RBM8afl/+mice show a significant decrease in the density of parvalbumin (PV)+ and neuropeptide Y (NPY)+ interneurons in the cortex, and PV+, NPY+ and somatostatin (SST)+ cells are abnormally distributed throughout the cortical layers. To determine the mechanism underlying this phenotype, we injected EdU into pregnant dams when the pups are E17 to label and quantitate the number of proliferating cells in the medial ganglionic eminence, where interneuron progenitors reside. We found a significant decrease in the number of cells in the S phase of the cell cycle. However, we did not observe any change in the number or distribution of Edu+/Nkx2.1+ progenitors (which become cortical interneurons). This indicates that the changes iv in interneuron number and distribution seen in adolescent mice (P17) are likely due to defects in proliferation migration of Nkx2.11+ progenitors from the GE to the cortex, or changes in cell fate. We then utilized Nkx2.1-cre mice to determine if the interneuron deficits were due to intrinsic changes in the progenitors, or due to cues received from other altered cell types. We determined that knockout of RBM8a in interneuron progenitors alone led to some changes in their distribution, but this effect was significantly less profound as when compared to the deletion of RBM8a from all neural stem cells (NSC)s. Therefore, we concluded that the phenotype is likely caused by some changes in intrinsic properties of Nkx2.1+ interneuron progenitors, but conceivably could also be due to changes in extrinsic cues from excitatory neurons and other cell types. To determine if pyramidal cells of the cortex have normal electrophysiological properties, we conducted spontaneous postsynaptic currents from putative pyramidal cells in the somatosensory cortex of Nes-cre;RBM8afl/+ mice and RBM8afl/+controls. Pyramidal cells of knockout mice show a significant decrease in the spontaneous inhibitory postsynaptic current (sIPSC) frequency, but no changes in sIPSC amplitude, or spontaneous excitatory postsynaptic current (sEPSC) frequency or amplitude. This suggests that there are functional deficits in the presynaptic, but not postsynaptic neurons. Deficits could include reduced activity of presynaptic interneurons, reduced number of synapses, or a lower vesicle release probability. Given our findings that these mice have fewer PV+ and NPY+ cells, we posit that cortical interneurons are releasing normal amounts of GABA, indicating that the change in frequency results from the decrease in interneuron number. However, more experiments need to be completed to clarify this point, including but not limited to evaluating miniature IPSCs (mIPSCs) and mEPSCs. Analyses of the transcriptome of mice with decreased RBM8a expression, and SH-SY5Y cells with RBM8a overexpressed indicated that RBM8a modulates many developmental v pathways, such as the extracellular matrix (ECM) pathway, growth factor signaling and Notch signaling. Additionally, our findings indicate that RBM8a is a moderate regulator of alternative splicing, and regulates transcripts with characteristics predisposing them to degradation via NMD (intron in the 3’ UTR, long 3’ UTR etc.). We further assessed the mechanisms behind the observed phenotypes by quantitative western blotting of synaptic and developmental pathway proteins to determine if any were differentially expressed in RBM8a mutants vs. controls. We identified decreased expression of the GluA1 subunit of AMPA receptors and β3 subunit of GABAA receptors in P17 whole brain lysate, and interestingly a 50% reduction in Notch1 NICD (Notch1 intracellular domain) expression. These results could explain the deficits observed in the knockout mice, however further research is needed to conclusively support this statement. Taken together, these data indicate a critical role for RBM8a in interneuron development, and establish that perturbation of this gene leads to profound developmental defects of the cerebral cortex. vi TABLE OF CONTENTS List of Figures .......................................................................................................................... ix List of Tables ........................................................................................................................... xi List of Abbreviations.................................................................................................................xii Acknowledgements .................................................................................................................. xiv Chapter 1 Background ............................................................................................................. 1 1.1 Cortical Development ................................................................................................ 1 1.1.1 Cell Cycle Regulation ..................................................................................... 3 1.1.2 Determination of stemness .............................................................................. 4 1.1.3 Neurogenesis ................................................................................................... 6 1.1.4 Interneuron Development ................................................................................ 7 1.1.5 Disruptions in neurogenesis ............................................................................ 9 1.2 RNA Stability and Neurodevelopment ...................................................................... 11 1.3 RNA Surveillance Mechanisms ................................................................................. 12 1.4 Clinical Phenotypes Caused by RBM8a .................................................................... 14 1.5 EJC Proteins and Neurodevelopment ......................................................................... 15 Chapter 2 Materials and Methods ............................................................................................ 17 2.1 Materials..................................................................................................................... 17 2.1.1 Antibodies used in this study........................................................................... 17 2.2 Methods ...................................................................................................................... 20 2.2.1 Mice ................................................................................................................. 20 2.2.2 Immunohistochemistry .................................................................................... 21 2.2.3 Organ Measurements ....................................................................................... 22 2.2.4 Western Blot .................................................................................................... 23 2.2.5 Cell Culture ..................................................................................................... 23 2.2.6 In utero electroporation .................................................................................. 24 2.2.7 RNAseq ........................................................................................................... 24 2.2.8 DNA construct, Transfection and Lentivirus production ................................ 27 2.2.9 Slice Electrophysiology ..................................................................................
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