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Characterization of the Role of Mouse Nell1 Gene in Osteogenesis and Chondrogenesis During Mammalian Fetal Development

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Characterization of the Role of Mouse Nell1 Gene in Osteogenesis and Chondrogenesis During Mammalian Fetal Development University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 8-2007 Characterization of the Role of Mouse Nell1 Gene in Osteogenesis and Chondrogenesis During Mammalian Fetal Development Jayashree Basavaraj Desai University of Tennessee - Knoxville Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Life Sciences Commons Recommended Citation Desai, Jayashree Basavaraj, "Characterization of the Role of Mouse Nell1 Gene in Osteogenesis and Chondrogenesis During Mammalian Fetal Development. " PhD diss., University of Tennessee, 2007. https://trace.tennessee.edu/utk_graddiss/153 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Jayashree Basavaraj Desai entitled "Characterization of the Role of Mouse Nell1 Gene in Osteogenesis and Chondrogenesis During Mammalian Fetal Development." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the requirements for the degree of Doctor of Philosophy, with a major in Life Sciences. Cymbeline T. Culiat, Major Professor We have read this dissertation and recommend its acceptance: Bruce McKee, Brynn Voy, Yisong Wang Accepted for the Council: Carolyn R. Hodges Vice Provost and Dean of the Graduate School (Original signatures are on file with official studentecor r ds.) To the Graduate Council: I am submitting herewith a dissertation written by Jayashree Basavaraj Desai entitled “Characterization of the Role of Mouse Nell1 Gene in Osteogenesis and Chondrogenesis During Mammalian Fetal Development.” I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the requirements for the degree of Doctor of Philosophy, with a major in Life Sciences. Cymbeline T. Culiat __________________ Major Professor We have read this dissertation And recommend its acceptance: Bruce McKee _________________________ Brynn Voy _________________________ Yisong Wang _________________________ Accepted for the Council: Carolyn R. Hodges ____________________ Vice Provost and Dean of the Graduate School (Original signatures are in the file with official student records) Characterization Of The Role Of Mouse Nell1 Gene In Osteogenesis And Chondrogenesis During Mammalian Fetal Development A Dissertation Presented for the Doctor of Philosophy Degree The University of Tennessee, Knoxville Jayashree Basavaraj Desai August 2007 Copyright© 2007 by Jayashree Desai All rights reserved ii DEDICATION This dissertation is dedicated to my family, my grandparents, Basavantrao and Laxmi Desai for raising me and for their endless love and support; to my parents, Jagadevrao and Uma Deshmukh for their love and for instilling in me the importance of higher education; to my wonderful sister, Sheela Prathap for always being there for me and to my beautiful nieces, Tejesvini, Prarthana and Prerana for their love and the joy they have given me. iii ACKNOWLEDGEMENTS I would like to thank the people who helped me to make this research and degree possible. First I would like to thank my advisor Dr. Cymbeline Culiat for her guidance, support, patience, and for introducing me to the world of mouse genetics. I would like to thank Dr. Bruce McKee, Dr. Brynn Voy, and Dr. Yisong Wang for their willingness to serve on my committee and for their invaluable input, advice and support. I like to especially thank Dr.Voy for her kindness, encouragement and positive attitude. Special thanks to Dr. Donald Torry, my previous mentor, for teaching me how to be a better graduate student and a scientist. Without his guidance and training I would not be here today. Also I would like to thank Dr. Jeffery Becker, the head of the department of Microbiology and the former director of graduate school of Genome Science and Technology for always believing in me and for his help, support and advice on countless occasions. I would like to thank my lab mates, Beverley Stanford, Marilyn Kerley and Lori Hughes for their friendship, support and help all through this journey. Lori, I especially thank you for teaching me how to do the animal work and helping me with the project. I would also like to thank all the members of the Mammalian Genetics and Functional Genomics Group (Oak Ridge ‘Mouse House’) for their technical support. Ingrid and Pushan, thank you for everything. Ingrid, I cannot thank you enough for your friendship, support and believing in me and above all being in my life and for just being who you are. Last but not least, my husband Raj, thank you for your support. Without you I would not have been able to achieve this goal. I would also like to thank my and Raj’s family in India for their love and support. iv ABSTRACT The mammalian Nell1 gene encodes a PKC-β1 binding protein that belongs to a new class of cell-signaling molecules controlling cell growth and differentiation. Overexpression of NELL1/Nell1 in the developing cranial sutures in both human and mouse induces craniosynostosis, the premature fusion of cranial sutures. This study describes the characterization of Nell16R (102DSJ), a recessive, neonatal-lethal point mutation in the mouse Nell1 gene, induced by N-ethyl-N-nitrosourea (ENU). The generation and sequencing of the mouse full-length cDNA (2862 bp) revealed that the Nell1 gene has an open reading frame of 2433 bp and encodes an 810 amino acid protein which is highly homologous to human and rat NELL1. Nell16R has a T→A base change that converts a codon for cysteine into a premature stop codon, resulting in severe truncation of the predicted protein product and marked reduction in steady state levels of the transcript. Immuno-histochemical analysis indicates that Nell1 is expressed in the vertebral column and is involved in osteoblast and chondrocyte differentiation. In addition to the expected alteration of cranial morphology, Nell16R mutants manifest skeletal defects in the vertebral column and ribcage, revealing a hitherto undefined role for Nell1 in signal transduction in endochondral ossification. Real-time quantitative RT- PCR assays of 219 genes showed an association between the loss of Nell1 function and reduced expression of genes for extracellular matrix proteins critical for chondrogenesis and osteogenesis. Several affected genes are involved in the human cartilage disorder known as Ehlers-Danlos Syndrome (EDS) and other disorders associated with spinal curvature anomalies. Nell16R mutant mice are a new tool for elucidating basic mechanisms in osteoblast and chondrocyte differentiation in the developing skull and vertebral column and understanding how perturbations in the production of extracellular matrix proteins can lead to anomalies in these structures. The characterization of Nell1 functions using the Nell16R mouse model may further provide insights into the pathology of craniofacial defects like CS, cartilage diseases such as EDS as well as other bone and cartilage diseases. v TABLE OF CONTENTS Chapter Page Chapter 1 ……………………………………………………………………………….. 1 Introduction ……………………………………………………………………………… 1 Chapter 2 ……………………………………………………………………………….. 5 Literature review ………………………………………………………………………… 5 Vertebrate skeleton …………………………………………………………………... 5 Bone ………………………………………………………………………………. 5 Cartilage …………………………………………………………………………... 7 Skeletogenesis ………………………………………………………………………... 8 Intramembranous ossification …………………………………………………… 11 Endochondral ossification ……………………………………………………….. 13 Development of axial skeleton ..……………………………………………… 15 Molecular basis for bone and cartilage formation ………………………………….. 16 Transcription factors …………………………………………………………….. 17 Osteoblast specific factor (Osf-2) ……………………………………………. 17 Msx-2 ………………………………………………………………………… 19 Extracellular matrix (ECM) proteins ……………………………………………. 20 Collagens …………………………………………………………………….. 20 Non-Collagenous extracellular matrix proteins ……………………………… 24 Bone morphogenetic proteins (BMP) and BMP receptors ……………………… 34 NELL1: a novel cell differentiation signaling protein in bone and cartilage development ……………………………………………………………………….... 36 Gene and protein structure ………………………………………………………. 36 Expression profile in humans and mouse ……………………………………….. 37 Gene regulation and associated pathway(s) ……………………………………... 38 Functions ………………………………………………………………………… 39 vi Chapter Page Protein kinase C signaling pathways and its relationship to NELL1 ……………. 41 Protein kinase C (PKC) ………………………………………………………. 41 Bone and cartilage disorders associated with NELL1-mediated pathways …………. 44 Craniosynostosis (CS) …………………………………………………………… 44 Ehlers-Danlos syndrome (EDS) …………………………………………………. 47 N-ethyl-N-nitrosourea (ENU) mutagenesis ………………………………………… 48 Chapter 3 ……………………………………………………………………………… 50 Materials and methods …………………………………………………………………. 50 Mouse breeding and maintenance …………………………………………………... 50 Generation of mutant hemizygotes and homozygotes for DSJ line ……………... 50 Collection mouse embryos ………………………………………………………….. 51 Genotyping of wild-type and l7R6R mutants ………………………………………... 54 Isolation of total and mRNA ………………………………………………………... 54 Nell1 gene profiling by northern blot and RT-PCR …………………………………
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