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The Identification of Molecular Guidance Cues Necessary for Development of the Central Auditory System

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The Identification of Molecular Guidance Cues Necessary for Development of the Central Auditory System Graduate Theses, Dissertations, and Problem Reports 2009 The identification of molecular guidance cues necessary for development of the central auditory system David M. Howell West Virginia University Follow this and additional works at: https://researchrepository.wvu.edu/etd Recommended Citation Howell, David M., "The identification of molecular guidance cues necessary for development of the central auditory system" (2009). Graduate Theses, Dissertations, and Problem Reports. 2839. https://researchrepository.wvu.edu/etd/2839 This Dissertation is protected by copyright and/or related rights. It has been brought to you by the The Research Repository @ WVU with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you must obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in WVU Graduate Theses, Dissertations, and Problem Reports collection by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. The Identification of Molecular Guidance Cues Necessary for Development of the Central Auditory System David M. Howell Dissertation submitted to the School of Medicine at West Virginia University In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biochemsitry and Molecular Biology Committee Members: Peter H. Mathers, Ph.D., Chair Albert S. Berrebi, Ph.D. Lisa Salati, Ph.D. Maxim Sokolov, Ph.D. George A. Spirou, Ph.D. Department of Biochemistry Morgantown, West Virginia 2009 Keywords: cochlear nucleus, medial nucleus of the trapezoid body, netrin, DCC, superior olivary complex, development Abstract The Identification of Molecular Guidance Cues Necessary for Development of the Central Auditory System David M. Howell Developing neurons utilize multiple guidance cues to reach their appropriate destination. Although much is known about the anatomy and electrophysiology of auditory brainstem neurons, the molecular factors directing migration of these cells and the targeting of their axons are only beginning to be explored. Ventral cochlear nucleus (VCN) neurons have axons that project bilaterally to the superior olivary complex (SOC) in the ventral acoustic stria (VAS). The circumferential trajectory taken by developing VCN axons is similar to the path of spinal commissural neurons (SCNs). Therefore, we reasoned that netrin-DCC and slit-robo signaling systems may function, similar to SCNs, in the guidance of VCN axons. We found that VCN axons extend toward the midline as early as E13, with many axons crossing the midline by E14.5. During this interval, netrin-1 and slit-1 RNAs are expressed at the brainstem midline, VCN neurons express RNAs for DCC, robo-1 and robo-2 receptors and VCN axons in the VAS are immunoreactive for DCC. Additionally, VCN axons fail to reach the midline in netrin-1- or DCC-deficient mice. The lack of VCN axonal outgrowth in DCC-deficient mice is not explained by the modest reduction (~ 10 %) of VCN neurons. Taken together, these data show that a functional netrin-DCC signaling system is required for establishing proper VCN axonal projections in the auditory brainstem. During our characterization of VCN axonal projections, we found that the neurons comprising the medial nucleus of the trapezoid body (MNTB), a component of the SOC, are absent in mice carrying no functional netrin-1 or DCC alleles. Since DCC is known to direct cellular migration in other regions of the central nervous system, we hypothesized that netrin-DCC and slit-robo signaling systems may function in the migration and positioning of MNTB neurons. RNAs for DCC, robo-1 and robo-2 are expressed in columns of cells that extend from the rostral brainstem to the developing SOC. MNTB and other superior olivary complex (SOC) neurons maintain expression of these guidance receptors during the formation of discreate SOC nuclei. Additionally, mice carrying only one functional copy of the netrin-1 or DCC allele have a laterally displaced MNTB and express half the quantity of DCC found in wild-type animals. The displaced MNTB is maintained in adult animals carrying only one functional DCC allele and is not explained by a difference in the number of MNTB neurons, as determined by unbiased stereology. In addition, the trochlear nucleus and ventral tegmental nucleus are significantly displaced, medially and laterally, respectively, in these adult heterozygous animals. We found that the tonotopic organization of the laterally displaced MNTB is preserved in mice carrying only one functional DCC allele. Therefore, these auditory circuits have sufficient plasticity to properly form in the presence of a significantly displaced MNTB. We propose that netrin-DCC and slit-robo signaling is necessary for the migration of SOC neurons and that medial-to-lateral positioning of the SOC and other central nervous system nuclei occurs in a dose-dependent manner, based on a cell’s programmed response to midline signals. This work will have clinical implications for future research in the repair/regeneration of central nervous system circuits. Dedication This work is dedicated to the memory of my father, Peter M. Howell, who passed away on January 18, 1991. iv Acknowledgements I would like to thank my advisor, Dr. Peter Mathers, for all of the advice, encouragement and support that he has provided me over the years. He fostered an environment of learning and gave me sufficient freedom to develop my project along lines that I found interesting and rewarding. The breadth of training that I received has greatly enhanced my development as a scientist. I will always be grateful for these reasons and many others. I would also like to thank the members of my committee, Dr. Albert Berrebi, Dr. Lisa Salati, Dr. Maxim Sokolov and Dr. George Spirou for all of their advice and time that they have provided over the years. They have helped me grow as a scientist and I am thankful for all the advice and support they have provided me. I would like to thank Dr. Janet Cyr for her participation and support that she has provided in the development of my project. I greatly appreciate all of the valuable contributions that were made by members of the labs with which I collaborated. I have truly benefited from these interactions and experiences with such a diverse group of colleagues. Finally, I would like to thank my family and friends that have supported me throughout the years. I am thankful for my mother, Martha, who has always provided me with love and support. I am thankful for my wife, Jodie, and our children, Lucas, Lauren and Alexandra, who continue to be a source of love and joy in my life. They have always been understanding and provided me with perspective and purpose. I could not have done this without the help from my family and friends. To everyone that has made this possible, I thank you all. v Table of contents Abstract................................................................................................................... ii Dedication...............................................................................................................iv Acknowledgments....................................................................................................v Table of Contents.................................................................................................... vi List of Figures ....................................................................................................... viii List of Abbreviations................................................................................................ ix CHAPTER 1: Introduction and Literature Review ...................................................1 Guidance factors.................................................................................................2 Netrins and their receptors..................................................................................2 Slits and their receptors ......................................................................................5 Integration of netrin and slit signaling..................................................................9 Eph receptors and their ephrin ligands .............................................................10 Morphogens......................................................................................................14 The hedgehog family ...................................................................................14 The decapentaplegic/bone morphogenic protein/transforming growth factor-β family ............................................................................................15 The wingless/Wnt family ..............................................................................16 The auditory system..........................................................................................17 Cochlear nucleus .........................................................................................17 Superior olivary complex..............................................................................19 Cochlear nucleus and superior olivary complex neurogenesis .........................21 Development of cochlear nucleus axons ..........................................................23 The calyceal
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