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Title:Regulatory dynamics of the Tbx18 locus in mouse urogenital development
Author(s):Bolt, Christopher Chase
Director of Research:Stubbs, Lisa J
Doctoral Committee Chair(s):Stubbs, Lisa J.
Doctoral Committee Member(s):Chen, Jie; Bolton, Eric; Smith-Bolton, Rachel; Robinson, Gene E.
Department / Program:Cell & Developmental Biology
Discipline:Cell and Developmental Biology
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Tbx18
Mouse
Prostate
Urogenital
Development
Genetics
Abstract:The mature mammalian urinary system includes the kidneys, ureters, bladder, and urethra. The kidneys produce urine that is then carried by the ureters to the bladder where it is stored. It is then released through the urethra. In males, the prostate develops at the junction of these structures from the prostatic rudiment, the urogenital sinus. Beginning in late gestation, the urogenital sinus begins differentiation under the influence of testicular androgens. Continuing from birth through puberty, the urogenital sinus grows and differentiates into the adult prostate. The urinary system and the prostate share many common properties including their basic structure, which consists of an epithelial layer that interacts with fluids, and a stromal smooth muscle layer that contracts to propel fluids through the organ. While the origin of the ureter and urogenital sinus epithelium are different, the mesenchymal cells that contribute to these structures are shared. The T-box transcription factor TBX18 is expressed in these mesenchymal cells and beginning at mid-gestation, Tbx18 expressing cells coalesce on the ureter and urogenital sinus epithelia, then differentiate into the smooth muscle layer. The loss of Tbx18 results in deformations and reduced function of the mature organs. To study the role of Tbx18 during the formation of ureter and prostate, we utilized a hypomorphic allele of Tbx18. This regulatory mutation, referred to as 12Gso, is relatively long- lived compared with Tbx18-null animals allowing us to assess the long-term impacts of Tbx18 loss-of-function in the urogenital system. Specifically, 12Gso is a chromosome translocation that separates an essential urogenital enhancer from Tbx18. In ureter development, the 12Gso allele is able to activate Tbx18 expression but is unable to maintain its expression for the appropriate amount of time. This results in a decrease in smooth muscle formation and impedes function of the ureter. This same mutation affects the formation of the urogenital sinus mesenchyme where Tbx18 cells suffer a similar fate as the ureter; that is, a loss of the prospective smooth muscle. Incredibly, the prostate stroma responds by hypertrophy and the adjacent epithelium responds by hyperplasia rather than hypotrophy and hypoplasia as occurs in the ureter. Through genome wide expression studies and chromatin immunoprecipitation experiments, we found Tbx18 to regulate potent cell-cycle effector genes and transcription factor genes oppositely in different cellular contexts, providing a partial explanation for Tbx18 loss-of-function phenotypes in these two tissues. Together, this work begins the dissection of the Tbx18 cis-regulatory structure by the identification of the ECR1 urogenital enhancer, it establishes the 12Gso mutation as a powerful tool in the evaluation of novel and post-natal phenotypes, and this work also provides a causal link between the Tbx18 loss-of-function phenotypes in several tissues by implicating Tbx18 in a mechanism that maintains proliferation of cells.
Issue Date:2015-04-20
Type:Thesis
URI:http://hdl.handle.net/2142/78608
Rights Information:Copyright 2015 Christopher Bolt
Date Available in IDEALS:2015-07-22
Date Deposited:May 2015


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