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Zebrafish Mutant Ninjaos5 Zebrafish mutant ninjaos5 (nij) is required for enteric neuron and craniofacial cartilage development and Zebrafish mutant hatchbackos20 (hbk) is required for trunk neural crest development. THESIS Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By Tamara Y. Robinson Graduate Program in Molecular, Cellular and Developmental Biology The Ohio State University 2010 Master's Examination Committee: Paul D. Henion “Advisor”, Susan Cole, Mark Seeger, James Jontes Copyright by Tamara Y. Robinson 2010 Abstract The neural crest (NC) is an ectoderm derived embryonic cell population that is specific to all vertebrate embryos. The NC is induced during gastrulation at the neural plate border (NPB) and migrates throughout the developing embryo to give rise to a number of derivatives including neurons and glia of the peripheral nervous system, pigment cells, and craniofacial cartilage and bone. Although much effort has been put into understanding neural crest diversification, the genetic regulatory network involved in this process is still not completely understood. The study of ENU induced zebrafish mutants with defective neural crest development is one approach that has been employed to address this issue. The zebrafish mutant ninjaos5(nij) is an ENU-induced, recessive, larval lethal mutation that was identified based on reduced cranial neural crest expression of crestin during embryogenesis. Reduced crestin expression in nij mutants is evident at hindbrain levels as well as in more anterior regions. NC precursors of the jaw elements are present in nij mutants, but neural crest derived elements of the craniofacial skeleton do not differentiate. In addition, we also find that enteric neuron precursors are severely reduced in nij mutants. As a result, very few cells are undergoing overt differentiation, accounting for the absence of enteric neurons. The development of other neural crest derivatives such as sensory neurons and chromatophores, in contrast, is comparatively normal. These results indicate an essential role for nij function in the development of the neural crest derived craniofacial skeleton and enteric nervous system. nij appears to be required for ii terminal differentiation of craniofacial cartilages and for establishment of enteric neurons precursors. The zebrafish mutant hatchback (hbk) is an ENU induced recessive embryonic lethal mutation that was identified based on reduced trunk neural crest expression of crestin. All zebrafish chromatophore cell types and trunk neuronal derivatives including enteric neurons, sympathetic neurons, and dorsal root ganglia are missing in hbk mutant embryos. In contrast, derivatives of cranial neural crest cells including the pharyngeal arches that give rise to the head skeleton, cranial satelite glia, and cranial ganglia are present. Assessment of early crest development reveals that the NPB and the NC are induced. However, pre-migratory NC expression of the early NC transcription factors that function in specification of neural crest sub-lineages is perturbed in the trunk. These results suggest that the function of hbk is required for specification of neural crest sub- lineages. iii Dedication This document is dedicated to my family. Thank you for your unconditional love and support. You are there through thick and thin, good or bad, right or wrong. I treasure you all and promise never to take you for granted. I love you dearly. iv Acknowledgment I would like to acknowledge my advisor Paul D. Henion for allowing me to become a member of his lab and introducing me to the world of science. The exposure I have received, laboratory experience I have obtained, the growth that has taken place, and the relationships I have developed would not have been possible if you had not given me a chance. Secondly I would like to thank you for encouraging, supporting, pushing me to go after what I want and pursue an alternative career path into medicine. This was a bitter sweet decision, but it is better to do what’s best for me than to conform to the expectations of others. I would also like to thank my committee James Jontes, Susan Cole, Mark Seeger, as well as Paul D. Henion. I would like to thank you all for your support and kindness. I have been blessed to be able to learn from such distinguished scientists. I want to also acknowledge my past and present lab mates, Marsha Lucas, Ph.D., Kevin Bosse, Arife Unal, Min An, Ph.D., Myron Ignatious, Ph.D., Brigitte Arduini, PhD., and Smitha Malireddy. My experience in this lab would not have been the same without you. Thanks for all your help, advice, encouragement, stimulating and sometimes random conversations, and laughs. I would also like to thank the members of the Beattie and Jontes lab. You too have been an integral part of my experience here at OSU. Thanks for all of your help and words of encouragement. v Vita June 2001…………………………………..Fairley High School, Memphis, TN 2005................................................................B.S. Biology, University of Arkansas at Pine Bluff 2006................................................................Graduate Teaching Associate, Department of Biological Sciences, Biology 101, Ohio State University 2005- to present .............................................Graduate Research Associate, Department of Molecular Cellular Developmental Biology, The Ohio State University Fields of Study Major Field: Molecular, Cellular and Developmental Biology vi Table of Contents Abstract............................................................................................................................... ii Dedication.......................................................................................................................... iv Acknowledgment ................................................................................................................ v Vita..................................................................................................................................... vi Fields of Study ................................................................................................................... vi Table of Contents.............................................................................................................. vii List of Figures..................................................................................................................... x List of Abbreviations ........................................................................................................ xii CHAPTER1 ........................................................................................................................ 1 Introduction......................................................................................................................... 1 1.1: Neural Crest Development: Neural Plate Border Induction .................................... 1 1.2: Neural Crest Development: Specification of Neural Crest Sub-lineages ................ 6 1.3: Neural Crest Development: Terminal Differentiation of Neural Crest Sub-lineages ......................................................................................................................................... 7 1.3.1: Terminal Differentiation: Pigment .................................................................... 7 1.3.2: Terminal Differentiation: Craniofacial Skeleton............................................... 9 1.3.3: Terminal Differentiation: Sympathetic Neurons............................................. 14 vii 1.3.4: Terminal Differentiation: Enteric Neurons ..................................................... 16 1.3.5: Terminal Differentiation: Dorsal Root Ganglia Sensory Neurons.................. 18 1.3.6: Terminal Differentiation: Conclusion ............................................................. 22 Chapter 2........................................................................................................................... 23 Characterization of the zebrafish mutant ninjaos5 (nij) ..................................................... 23 2.1 Introduction ............................................................................................................. 23 2.2: Isolation of zebrafish mutant nijos5......................................................................... 24 2.3 Zebrafish mutant nijos5 is required for craniofacial cartilage development............. 25 2.4 Zebrafish mutant nij is required for enteric neuron development........................... 29 2.5 Neural Plate Border (NPB) and Neural Crest Induction Are Unaffected in nijos5 .. 34 2.6 Enteric neuron and craniofacial abnormalities may be due to an increase in cell death. ............................................................................................................................. 35 2.7 Mapping of nijos5 ..................................................................................................... 37 2.8 Discussion ............................................................................................................... 38 2.9 Materials and Methods............................................................................................ 43 2.9.1 Zebrafish Husbandry ........................................................................................ 43 2.9.2 Whole mount in situ Hybridization and immunohistochemistry...................... 44 2.9.3 Alcian Blue Staining........................................................................................
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