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JAGGED-NOTCH SIGNALING: PATTERNING THE VERTEBRATE FACE
by
Elizabeth Zuniga
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(NEUROSCIENCE)
December 2012
Copyright 2012 Elizabeth Zuniga
Object Description
| Title | Jagged-notch signaling: patterning the vertebrate face |
| Author | Zuniga, Elizabeth |
| Author email | elizabez@usc.edu;elizabez5@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Neuroscience |
| School | Keck School of Medicine |
| Date defended/completed | 2012-09-26 |
| Date submitted | 2012-10-09 |
| Date approved | 2012-10-09 |
| Restricted until | 2012-10-09 |
| Date published | 2012-10-09 |
| Advisor (committee chair) | Crump, Gage D. |
| Advisor (committee member) |
Maxson, Robert E., Jr. Segil, Neil Butler, Samantha Ma, Le |
| Abstract | Craniofacial abnormalities are the most common birth defects, and yet little is known about the developmental etiology that leads to mispatterning of the face. Several studies have shown that the development of the face depends on the regionalization of neural crest precursors into distinct domains along the dorsoventral (DV) axis. Previous research has shown Endothelin 1 (Edn1) is required for patterning the ventral (lower) face, in part by regulating the expression of ventral genes such as those of the Dlx family. However, little is known about the factors required for development of the dorsal (upper) face. By analyzing a newly identified zebrafish jag1b mutant and transgenic overexpressing JAGGED1, we find that Jagged-Notch signaling promotes dorsal identity by repressing ventral gene expression. Jagged ligands are thought to act primarily as ligands for Notch receptors, with cleavage and nuclear translocation of a Notch intracellular domain (NICD) affecting gene transcription. Surprisingly, we find that transgenic misexpression of JAGGED1 intracellular domain (JICD), which lacks the extracellular domain required for Notch binding, produces facial skeletal and DV gene expression defects similar to those seen upon misexpression of full-length JAGGED1. These findings lead us to propose a novel cell-autonomous role for Jagged in transcriptional regulation responsible for patterning the dorsal face. Next, we identified the Bmp antagonist Gremlin2 as a target of both Jagged-Notch and Edn1 signaling with Grem2 being required to restrict Bmp activity to the ventral-most domain of the arches. Using gain- and loss-of-function studies, we revealed a complex genetic interaction among Jagged, Edn1, and Bmp signaling in specifying distinct skeletal fates along the DV facial axis. Taken all together, our findings are the first to show how Jagged is involved in regional patterning of the face. Mutations in Jagged are found in patients with Alagille syndrome who often have a characteristic facial dysmorphology. Thus determining how Jagged patterns the face will lead us closer in understanding how a disruption in this pathway results in facial anomalies in humans. |
| Keyword | craniofacial; Jagged1; Notch2; zebrafish; Edn1; Bmp |
| 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 |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Contributing entity | University of Southern California |
| Rights | Zuniga, Elizabeth |
| Physical access | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@lib.usc.edu |
| Archival file | uscthesesreloadpub_Volume4/etd-ZunigaEliz-1241.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | JAGGED-NOTCH SIGNALING: PATTERNING THE VERTEBRATE FACE by Elizabeth Zuniga A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (NEUROSCIENCE) December 2012 Copyright 2012 Elizabeth Zuniga |
