The role of hepatocyte nuclear factor 1 beta in kidney development and disease

Shao, Annie
2022-09
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The role of hepatocyte nuclear factor 1 beta in kidney development and disease

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2022-09

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The transcription factor hepatocyte nuclear factor 1β (HNF-1β) is essential for normal development of the kidney and other epithelial organs. Mutations of HNF1B in humans produce cystic kidney diseases, including congenital anomalies of the kidney and urinary tract (CAKUT) and autosomal dominant tubulointerstitial kidney disease (ADTKD). CAKUT is one of the most common birth defects and most common causes of pediatric end-stage renal disease. There are no curative treatments for CAKUT. Individuals with CAKUT may need lifelong dialysis or kidney transplant. CAKUT is caused by a perturbation of kidney development. Mammalian kidney development involves reciprocal cell signaling between two primordia: the metanephric mesenchyme (MM), which gives rise to nephrons, and the ureteric bud (UB), which gives rise to the collecting duct system. HNF-1β is required for the differentiation and patterning of immature nephrons and branching morphogenesis of the UB. Kidney-specific ablation of HNF-1β in mice during development causes branching morphogenesis failure and hypoplastic kidneys. In addition, kidney-specific ablation of HNF-1β after kidney development in mice leads to cystic kidney disease. In the studies presented here, we examined the role of HNF-1β in fibrosis in HNF1B-related ADTKD using transgenic mouse models and lineage tracing. We optimized ex vivo metanephric organ culture and 3D imaging as a method of quantifying UB branching morphogenesis and tested several gene manipulation strategies for ex vivo kidney culture. We used ChIP-sequencing (ChIP-seq) and RNA sequencing (RNA-seq) to identify genes that are regulated by HNF-1β in embryonic mouse kidneys. These studies found that HNF-1β directly regulates the expression of multiple axon guidance genes in the developing mouse kidney. Dysregulation of axon guidance genes may underlie kidney defects in HNF-1β mutant mice. We used ChIP-seq and RNA-seq to identify genes that are regulated by HNF-1β in adult mouse kidneys. We compared genes and pathways regulated by HNF-1β in adult and embryonic mouse kidneys. We found that HNF-1β also regulates axon guidance in adult kidneys. Collectively, these studies identify novel pathways HNF-1β regulates in the developing kidney and adult kidney whose dysregulation leads to kidney disease.

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University of Minnesota Ph.D. dissertation. September 2022. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: Peter Igarashi. 1 computer file (PDF); vii, 132 pages.

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Shao, Annie. (2022). The role of hepatocyte nuclear factor 1 beta in kidney development and disease. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/250031.

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