Functions of Zinc-finger Transcription Factors Gli and Osr during Foregut Development in Mouse

Bibliographic Details
Main Author:	Han, Lu
Language:	English
Published:	University of Cincinnati / OhioLINK 2017
Subjects:	Developmental Biology Hedgehog Gli Odd-skipped foregut endoderm mesenchyme
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504871878955264

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-ucin15048718789552642021-08-03T07:04:08Z Functions of Zinc-finger Transcription Factors Gli and Osr during Foregut Development in Mouse Han, Lu Developmental Biology Hedgehog Gli Odd-skipped foregut endoderm mesenchyme The trachea, lungs and esophagus derive from the anterior foregut and they are all composed of a single-cell layer of epithelial cells surrounded by various kinds of mesenchymal cells. The mesenchymal tissue provides critical instructive roles in epithelial development and also undergoes intricate patterning alongside the epithelium. Despite the broad knowledge of epithelial specification and differentiation, the molecular mechanisms guiding early foregut mesenchymal patterning and differentiation events are poorly understood. The dysregulation of those early developmental events could lead to severe congenital defects but the etiology of many such cases are completely unknown. The Hedgehog (HH) signaling pathway is a key regulator of multiple steps of foregut development. However, functions of the HH pathway during early foregut development and its downstream targets remain to be identified. In my thesis, I aimed to understand such molecular mechanisms of mesenchymal patterning and differentiation during early foregut development using mouse genetics and ex vivo culture systems. In chapter 2, I determine the functions of Hedgehog/Gli pathway during respiratory specification. I find that Hedgehog (HH) ligands are produced in the foregut epithelium and a robust HH response can be detected in the surrounding splanchnic mesenchyme during specification. A loss of function study using mouse mutants for the HH pathway effectors, Gli2 and Gli3, demonstrated the essential functions of HH activity in specifying the respiratory domain. We show that HH signaling in the mesenchyme is necessary for the respiratory-inducing signals Wnt2,2b and Bmp4. This work has been published in Cell Reports (Rankin et al. 2016). We further show that Gli2,3 are essential for maintaining the expression of several mesenchymal transcription factors, including Osr1. In Chapter 3, I identify Osr1 as a downstream target of the HH/Gli pathway and uncover the essential roles of Osr1 in supporting robust respiratory specification, accurate lobulation positions and mesenchymal differentiation in the foregut. Mesenchyme specific knockout of Osr1 using Dermo1-Cre in combination with lineage tracing of Osr1 expressing progenitors suggests that Osr1 is required in the mesenchyme. This work has been published in Developmental Biology (Han et al. 2017). These findings of the essential functions of the HH pathway and its downstream target Osr1 could be conserved in human development. They could be used to guide human stem cell engineering to model human development and physiology. 2017-12-05 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504871878955264 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504871878955264 unrestricted This thesis or dissertation is protected by copyright: some rights reserved. It is licensed for use under a Creative Commons license. Specific terms and permissions are available from this document's record in the OhioLINK ETD Center.
collection	NDLTD
language	English
sources	NDLTD
topic	Developmental Biology Hedgehog Gli Odd-skipped foregut endoderm mesenchyme
spellingShingle	Developmental Biology Hedgehog Gli Odd-skipped foregut endoderm mesenchyme Han, Lu Functions of Zinc-finger Transcription Factors Gli and Osr during Foregut Development in Mouse
author	Han, Lu
author_facet	Han, Lu
author_sort	Han, Lu
title	Functions of Zinc-finger Transcription Factors Gli and Osr during Foregut Development in Mouse
title_short	Functions of Zinc-finger Transcription Factors Gli and Osr during Foregut Development in Mouse
title_full	Functions of Zinc-finger Transcription Factors Gli and Osr during Foregut Development in Mouse
title_fullStr	Functions of Zinc-finger Transcription Factors Gli and Osr during Foregut Development in Mouse
title_full_unstemmed	Functions of Zinc-finger Transcription Factors Gli and Osr during Foregut Development in Mouse
title_sort	functions of zinc-finger transcription factors gli and osr during foregut development in mouse
publisher	University of Cincinnati / OhioLINK
publishDate	2017
url	http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504871878955264
work_keys_str_mv	AT hanlu functionsofzincfingertranscriptionfactorsgliandosrduringforegutdevelopmentinmouse
_version_	1719452939336024064

Functions of Zinc-finger Transcription Factors Gli and Osr during Foregut Development in Mouse

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