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The Investigation of Hydrocephalus in Mice Lacking the Transcription Factor NFIX Diana Vidovic Bsc (Hons)

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The Investigation of Hydrocephalus in Mice Lacking the Transcription Factor NFIX Diana Vidovic Bsc (Hons) The investigation of hydrocephalus in mice lacking the transcription factor NFIX Diana Vidovic BSc (Hons) A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2018 Faculty of Medicine 1 Abstract Hydrocephalus is a relatively common birth defect (Bruni, Del Bigio, & Clattenburg, 1985) but despite its prevalence, and the existence of several rodent models of this disorder (Jones & Bucknall, 1988; K. Lee et al., 2012; Perez-Figares et al., 1998), our understanding of the molecular and cellular mechanisms leading to the pathological cerebrospinal fluid (CSF) accumulation remains limited. This thesis has focused on investigating hydrocephalus in mice lacking Nuclear factor one X (NFIX). NFIX belongs to a group of site-specific transcription factors known as the Nuclear factor one gene (NFI) family. Preliminary data in mouse models has shown that NFIX is expressed by neural progenitor cells within the central nervous system (CNS) and that mice lacking this gene exhibit abnormal phenotypes within the rodent developing forebrain. Here we revealed that hydrocephalus is a consistent feature present in mice lacking the transcription factor Nfix, implicating normal NFIX function as being central to the formation of the intraventricular region of the central nervous system. Specifically, we have demonstrated that NFIX is central to the biology of ependymal cells, and that in its absence, the lateral ventricles of the dorsal telencephalon exhibit denudation of the ependymal cell layer. We have shown that Nfix deficient mice exhibit aberrant ependymal cell morphology at postnatal day (P) 15, culminating in abnormal thickening and sloughing of this cellular layer. Moreover, we showed that the expression of ependymal cell-specific markers was delayed. Finally, we revealed Foxj1, a key factor promoting ependymal cell maturation, as a target for NFIX-mediated transcriptional activation. Collectively, our data suggested that ependymal cell development may be reliant, at least in part, on NFIX expression, implicating this transcription factor as a mediator of ependymal cell biology. Owing to our limited knowledge of the genetics and molecular pathogenesis of human hydrocephalus, using data extrapolated from animal models may provide invaluable information regarding the development of this disease in humans. This may prove useful when considering strategies to harness better treatments, such as drug-based therapeutics, to treat patients with hydrocephalus and, to improve early diagnosis of this disorder. Therefore a better understanding of the pathogenesis and the underlying causes leading to the development of hydrocephalus are necessary. 2 Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, financial support and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my higher degree by research candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis and have sought permission from co-authors for any jointly authored works included in the thesis. 3 Publications during candidature Peer reviewed papers: Diana Vidovic, Lachlan Harris, Tracey J. Harvey, Yee Hsieh Evelyn Heng, Aaron G. Smith, Jason Osinski, James Hughes, Paul Thomas, Richard M Gronostajski, Timothy L Bailey, Michael Piper: Expansion of the lateral ventricles and ependymal deficits underlie the Hydrocephalus evident in mice lacking the transcription factor NFIX. Brain research 05/2015; 1616. DOI:10.1016/j.brainres.2015.04.057 Lachlan Harris, O. Zalucki, I. Gobius, H. McDonald, J. Osinki, T.J. Harvey, A. Essebier, D. Vidovic, I. Gladwyn-Ng, T.H. Burne, J.I. Heng, L.J. Richards, R.M. Gronostajski, M. Piper: Transcriptional regulation of intermediate progenitor cell generation during hippocampal development. Development 15/12/2016 DOI:10.1242/dev.140681 Jens Bunt, Jason M Osinski, Jonathan WC Lim, Diana Vidovic, Yunan Ye, Oressia Zalucki, Timothy R O’Connor, Lachlan Harris, Richard M Gronostajski, Linda J Richards and Michael Piper: Combined allelic dosage of Nfia and Nfib regulates cortical development. Brain and Neuroscience Advances. 01/10/2017 DOI: 10.1177/2398212817739433 journals.sagepub.com/home/bna Diana Vidovic, Raul Ayala Davila, Richard M. Gronostajski, Tracey J. Harvey and Michael Piper: Transcriptional regulation of ependymal cell maturation within the postnatal brain. Neural Development 13/02/2018; DOI:10.1186/s13064-018- Book Chapter: Diana Vidovic, Michael Piper and Tracey J. Harvey (2016) Ependymal cells in development and disease. In Merle Reeves (Ed.) Hydrocephalus: prevalence, risk factors and treatment. (pp. 39- 62) New York, NY, United States: Nova Science Publishers. 0099-4 4 Publications included in this thesis Incorporated as Chapter 1. Diana Vidovic, Michael Piper and Tracey J. Harvey (2016) Ependymal cells in development and disease. In Merle Reeves (Ed.) Hydrocephalus: prevalence, risk factors and treatment. (pp. 39-62) New York, NY, United States: Nova Science Publishers. Contributor Statement of contribution Diana Vidovic (Candidate) Conception and design (50%) Analysis and interpretation (0%) Drafting and production (50%) Tracey J. Harvey Conception and design (40%) Analysis and interpretation (0%) Drafting and production (40%) Michael Piper Conception and design (10%) Analysis and interpretation (0%) Drafting and production (10%) Incorporated as Chapter2. Diana Vidovic, Lachlan Harris, Tracey J. Harvey, Yee Hsieh Evelyn Heng, Aaron G. Smith, Jason Osinski, James Hughes, Paul Thomas, Richard M Gronostajski, Timothy L Bailey, Michael Piper: Expansion of the lateral ventricles and ependymal deficits underlie the Hydrocephalus evident in mice lacking the transcription factor NFIX. Brain research 05/2015; 1616. DOI:10.1016/j.brainres.2015.04.057 Contributor Statement of contribution Diana Vidovic (Candidate) Conception and design (90%) Analysis and interpretation (90%) Drafting and production (60%) Lachlan Harris Conception and design (4%) Analysis and interpretation (0%) Drafting and production (0%) Tracey J. Harvey Conception and design (5%) Analysis and interpretation (0%) 5 Drafting and production (0%) Yee Hsieh Evelyn Heng Conception and design (1%) Analysis and interpretation (0%) Drafting and production (0%) Aaron G. Smith Conception and design (<1%) Analysis and interpretation (0%) Drafting and production (0%) James Hughes Conception and design (<1%) Analysis and interpretation (0%) Drafting and production (0%) Paul Thomas Conception and design (0%) Analysis and interpretation (5%) Drafting and production (0%) Timothy L Bailey Conception and design (0%) Analysis and interpretation (<1%) Drafting and production (0%) Richard Gronostajski Conception and design (0%) Analysis and interpretation (0%) Drafting and production (10%) Michael Piper Conception and design (10%) Analysis and interpretation (5%) Drafting and production (30%) Incorporated as Chapter3. Diana Vidovic, Raul Ayala Davila, Richard M. Gronostajski, Tracey J. Harvey and Michael Piper: Transcriptional regulation of ependymal cell maturation within the postnatal brain. Neural Development 13/02/2018; DOI:10.1186/s13064-018-0099-4 Contributor Statement of contribution Diana Vidovic (Candidate) Conception and design (80%) Analysis and interpretation (90%) Drafting and production (70%) Tracey J. Harvey Conception and design (10%) Analysis and interpretation (5%) 6 Drafting and production (0%) Raul Ayala Davila Conception and design (5%) Analysis and interpretation (0%) Drafting and production (0%) Richard M. Gronostajski Conception and design (0%) Analysis and interpretation (0%) Drafting and production (10%) Michael Piper Conception and design (5%) Analysis and interpretation (5%) Drafting and production (20%) 7 Contributions by others to the thesis Chapter 2 Yee Hsieh Evelyn Heng performed the imaging of the whole wild-type and Nfix mutant mice, and the haematoxylin staining of the sagittal SVZ brain sections in Figure 2.1 Tracey J. Harvey assisted with the luciferase experiment in Figure 2.7 and performed the QPCR experiment for Figure 2.15 Lachlan Harris performed the imaging for Figure 3.13 Statement of parts of the thesis submitted to qualify for the award of another degree Some of the data
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