Download the full-sized PDF of Molecular and cellular analysis of skeletal muscle and neuronal development in a necdin-null mouse model of Prader-Willi syndromeDownload the full-sized PDF



Permanent link (DOI):


Export to: EndNote  |  Zotero  |  Mendeley


This file is in the following communities:

Graduate Studies and Research, Faculty of


This file is in the following collections:

Theses and Dissertations

Molecular and cellular analysis of skeletal muscle and neuronal development in a necdin-null mouse model of Prader-Willi syndrome Open Access


Other title
Prader-Willi, myogenesis, differentiation, migration, polarity, myosin
Type of item
Degree grantor
University of Alberta
Author or creator
Bush, Jason Russell
Supervisor and department
Wevrick, Rachel (Medical Genetics)
Examining committee member and department
Underhill, D. Alan (Oncology and Medical Genetics)
Eisenstat, David (Pediatrics & Child Health, Human Anatomy & Cell Science, Biochemistry & Medical Genetics, and Ophthalmology, University of Manitoba)
Pilgrim, David (Biological Sciences and Cell Biology)
Berry, Fred (Medical Genetics)
Medical Sciences - Medical Genetics

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Prader-Willi syndrome (PWS) is a recurrent microdeletion syndrome characterized by severe obesity, hyperphagia, hypotonia, and developmental delay, and is caused by the loss of expression of four protein-coding genes and set of small nucleolar RNAs on chromosome 15. NDN, encoding the protein necdin, is one of these genes, and a large body of literature supports the theory that necdin is important for the differentiation and survival of neurons. Given that necdin is also abundant in developing muscle and that hypotonia is a cardinal feature of PWS, I hypothesize that necdin promotes normal skeletal muscle development. I provide two lines of evidence demonstrating that loss of necdin impairs muscle development in mice. First, necdin interacts with the inhibitor of muscle differentiation EID-1 to relieve inhibition of MyoD-dependent transcription by sequestering this protein in the cytoplasm in over-expression assays. Unexpectedly, the presence of necdin increases EID-1 protein abundance in transfected cells and endogenous EID-1 is less abundant in Ndn-null embryonic mouse tissue compared to controls. Finally, conversion from MyoD+ to Myosin Heavy Chain+ cells is impaired in limb bud cultures from Ndn-null embryos, consistent with the hypothesis that loss of necdin impairs muscle differentiation by failing to relieve EID-1-dependent transcriptional inhibition. Second, loss of necdin impairs polarization of muscle progenitors in vitro and in vivo due to failed activation of the actin-myosin cytoskeleton, and reduces the proportional area of forelimb extensor muscles in Ndn-null mice at birth. This conclusion is supported by defective centrosome re-orientation due to impaired nuclear rearward movement and failed Cdc42 activation in Ndn-null mouse embryonic fibroblasts (MEFs), impaired myosin activation in Ndn-null MEFs and cortical neurons, and excessive branching and failure of hippocampal neurons to polarize with respect to a growth factor. Additionally, PWS patient fibroblasts display centrosome re-orientation defects and impaired myosin activation identical to Ndn-null MEFs, indicating that loss of necdin produces a similar phenotype in both mice and humans. These results provide strong evidence that necdin is critical for both the migration and primary differentiation of skeletal muscle, and validates the Ndn-null mouse as a model for hypotonia in PWS.
License granted by Jason Bush ( on 2010-08-31T20:30:08Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication

File Details

Date Uploaded
Date Modified
Audit Status
Audits have not yet been run on this file.
File format: pdf (Portable Document Format)
Mime type: application/pdf
File size: 22010334
Last modified: 2015:10:12 16:37:50-06:00
Filename: Bush_Jason_Fall2010.pdf
Original checksum: 644da500c542c132831acf1e34782e0c
Well formed: true
Valid: true
Status message: File header gives version as 1.4, but catalog dictionary gives version as 1.3
File title: Microsoft Word - JRB thesis final.doc
File author: Jason Bush
Page count: 299
Activity of users you follow
User Activity Date