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LINEAGE BOUNDARIES AND CELL MIGRATION IN THE
PATTERNING OF THE MAMMALIAN SKULL
by
Man-Chun Ting
_____________________________________________
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
August 2008
Copyright 2008 Man-Chun Ting
Object Description
| Title | Lineage boundaries and cell migration in the patterning of the mammalian skull |
| Author | Ting, Man-Chun |
| Author email | manchunt@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Biochemistry & Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2008-06-18 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-07-24 |
| Advisor (committee chair) | Maxson, Robert E. |
| Advisor (committee member) |
Stallcup, Michael R. Sucov, Henry |
| Abstract | Eph-ephrin signaling has been implicated in craniosynostosis in humans: Mutations in the ephrin ligands, EFNA4 and EFNB1, are known to cause craniosynostosis. Our present work shows that Twist and Msx2, also craniosynostosis genes, interact functionally with the Eph-ephrin signaling pathway. Reduced expression of ephrinA2, ephrinA4 and EphA4 in a layer of cells located along the neural-crest mesoderm boundary was previously described associating with the upregulated expression of Msx2 in osteogenic mesenchyme and expanded into the non-osteogenic mesoderm domain in Twist mutants. And the expression of Eph-ephrin genes, as well as the boundary defect, can be rescued by genetic inactivation of Msx2 in the context of the Twist+/- genotype. Here we demonstrate that EphA4 mutant mice phenocopy Twist mutants: Wnt1-Cre and Mesp1-Cre marking of neural crest and mesoderm show that EphA4 mutant embryos exhibit defects in the neural crest-mesoderm boundary within the coronal suture. Osteogenic neural crest-derived cells mix with non-osteogenic mesodermal cells fated to form the suture. Associated with this mixing is the development of ectopic bone in the suture.; Further, genetic inactivation of a Twist allele in the context of EphA4 exacerbated both the boundary and synostosis phenotypes. By labeling migratory osteogenic cells that contribute to the frontal and parietal bones, we showed that Twist and EphA4 are required for the exclusion of osteogenic cells from the coronal suture. Finally, to elucidate the mechanism of spatial and temporal control of Eph-ephrin expressions, we characterized murine EphA4 and ephrin-A4 cis-regulatory elements by using phylogenetic footprinting approaches. Comparative genomic analysis revealed conserved blocks surrounding EphA4 and ephrinA4 genomic regions with putative Twist and Msx2 binding sequences. ChIP analysis provided evidence Twist and/or Msx2 interact directly with conserved genomic regions of EphA4 and ephein-A4. Together these data suggest that Twist and Eph-ephrin signaling in a network controls the frontal-parietal boundary and coronal suture development. |
| Keyword | craniosynostosis; Twist; EphA4 |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m1387 |
| Contributing entity | University of Southern California |
| Rights | Ting, Man-Chun |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@dots.usc.edu |
| Filename | etd-Ting-20080724 |
| Archival file | uscthesesreloadpub_Volume17/etd-Ting-20080724.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@dots.usc.edu |
| Full text | LINEAGE BOUNDARIES AND CELL MIGRATION IN THE PATTERNING OF THE MAMMALIAN SKULL by Man-Chun Ting _____________________________________________ A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (BIOCHEMISTRY AND MOLECULAR BIOLOGY) August 2008 Copyright 2008 Man-Chun Ting |
