Whole or Hole? Development of the Diaphragm and Congenital Diaphragmatic Hernias

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Publication Type dissertation
School or College School of Medicine
Department Human Genetics
Author Merrell, Allyson Jean
Title Whole or Hole? Development of the Diaphragm and Congenital Diaphragmatic Hernias
Date 2014-08
Description The mammalian diaphragm is the most critical skeletal muscle and defects in the development of the diaphragm give rise to congenital diaphragmatic hernias (CDH), which are common and frequently lethal birth defects. The diaphragm has been proposed to develop from multiple embryonic sources, but how these sources are integrated to form the diaphragm and how defects in diaphragm development induce CDH is poorly understood. Using mouse genetics we demonstrate that the pleuroperitoneal folds (PPF), transient developmental structures, will give rise to connective tissue fibroblasts throughout the diaphragm. Furthermore, we show that the PPFs non-cell autonomously regulate the somitically-derived muscle of the diaphragm and control the morphogenesis of the diaphragm. Deletion of candidate CDH genes, Gata4 and Porcn, specifically within the PPF generates CDH with 100% penetrance, demonstrating that the PPFs are the cellular source of CDH defects. Deletion of Gata4 in the PPF causes early defects in muscle progenitor number and localization, creating amuscularized regions that will form CDHs. Interestingly, PPF-specific deletion of Porcn, which is required for secretion of Wnt ligand, produces late defects in diaphragm development and prevents the diaphragm muscle from spreading completely to the most ventral region of the diaphragm. This demonstrates that Wnt signals from the PPF are critical for the formation of the ventral muscle of the diaphragm. Furthermore, we propose that signals from the PPF may be critical for inducing muscle precursors to migrate from the somites to the diaphragm and acquisition of these signals may have allowed evolution of the muscularized mammalian diaphragm. This work demonstrates the essential roles of the PPF-derived connective tissue fibroblasts in all steps of diaphragm development.
Type Text
Publisher University of Utah
Subject MESH Fetal Development; Hernias, Diaphragmatic, Congenital; Growth and Development; Morphogenesis; Diaphragm; COUP Transcription Factor II; GATA4 Transcription Factor; Gene Expression Regulation, Developmental; Transcription Factors; Congenital Abnormalities; Cell Differentiation
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital reproduction of Whole or Hole? Development of the Diaphragm and Congenital Diaphragmatic Hernias
Rights Management Copyright © Allyson Jean Merrell 2014
Format Medium application/pdf
Format Extent 6,432,838 bytes
Source Original in Marriott Library Special Collections
ARK ark:/87278/s6m08jmt
Setname ir_etd
Date Created 2019-03-11
Date Modified 2021-05-06
ID 1404034
Reference URL https://collections.lib.utah.edu/ark:/87278/s6m08jmt
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