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Making one lip and nose from two: morphogenetic mechanisms of anterior midface convergence modeled in Unicorn and Beetlejuice mice

Lantz, Brandi (2018) Making one lip and nose from two: morphogenetic mechanisms of anterior midface convergence modeled in Unicorn and Beetlejuice mice. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Orofacial clefting is the most common craniofacial anomaly and consists of several distinct phenotypic categories that range from lateral to medial facial clefts (MFCs). MFCs range in severity from a small medial notch in the vermillion of the upper lip, to a large medial cleft lip that extends posteriorly through the alveolar ridge and secondary palate and anteriorly through the nose. In humans MFCs are rare, thus there is a paucity of animal models and hypotheses surrounding the molecular and morphogenetic etiology of MFCs. During normal development, the anterior midface develops from the medial convergence of paired medial nasal prominences (MNPs) forming the midline of the upper lip and nose. Failure of MNP convergence results in MFCs.
To understand MFCs at both ends of the phenotypic spectrum, I compared the development of the mild medial soft tissue cleft lip in Prickle1Bj/Bj embryos and the severe MFC in Unicorn embryos. Unicorn embryos develop a MFC that splits the nose into two independent nostrils and extends from the medial lip to the secondary palate. I observed the frontonasal ectodermal zone, a signaling center that is required for normal outgrowth of the upper face, is displaced posteriorly in Unicorn mutants resulting in the development of two independent nostrils supported by a bifurcated nasal septum. In normal embryos, I observed an epithelial to mesenchymal transformation (EMT) occurs in the medial MNP epithelium during medial convergence. I observed that both the Prickle1Bj/Bj and Unicorn medial MNP epithelia has decreased apical-basal polarity and failed to undergo EMT by E11.5, the stage of completion in control embryos.
Furthermore, I used histological analysis in wildtype animals, as well as, lineage tracing with an inducible cartilage-specific Cre recombinase (Collagen2-creERT) driver to describe normal nasal septum development. These experiments revealed that the nasal septum begins developing as two independent rods of Collagen2-Cre positive cells approximating the midline of the MNPs as early as E10.5. By E11.5, the Collagen2-cre positive rods are fusing together in the anterior to posterior direction resulting in a single nasal septum.
In conclusion, my work has uncovered novel morphological and genetic mechanisms that control midfacial convergence.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Lantz, Brandibrg77@pitt.edubrg77
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSzabo-Rogers, Heatherhsrogers@pitt.eduhsrogers
Committee MemberTaboas, Juanjmt106@pitt.edujmt106
Committee MemberWeinberg, Sethsmwst46@pitt.edusmwst46
Committee MemberDavidson, Lancelad43@pitt.edulad43
Date: 14 August 2018
Date Type: Publication
Defense Date: 17 July 2018
Approval Date: 14 August 2018
Submission Date: 13 August 2018
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 187
Institution: University of Pittsburgh
Schools and Programs: School of Dental Medicine > Dental Science
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: midfacial clefting, nasal septum morphogenesis
Date Deposited: 14 Aug 2018 13:21
Last Modified: 14 Aug 2018 13:21
URI: http://d-scholarship.pitt.edu/id/eprint/35193

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