Chad PopeFollow

Date of Completion

7-31-2017

Embargo Period

7-31-2018

Keywords

cell proliferation, H19, lncRNA, liver maturation

Major Advisor

Dr. Xiaobo Zhong

Associate Advisor

Dr. Jose Manautou

Associate Advisor

Dr. Theodore Rasmussen

Associate Advisor

Dr. R Scott Obach

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Liver development at the postnatal age has been understudied despite being a time when the liver is rapidly growing and changing its primary function as an organ involved in hematopoiesis to an organ responsible for metabolism. Long non-coding RNAs (LncRNAs) are important in many biological processes, including organogenesis, normal liver functions, and liver diseases. Expression levels of lncRNAs change in identifiable patterns in liver during development, and H19, due to its expression pattern, may be important for liver development.

H19 RNA is highly expressed at early postnatal ages and precipitously decreases at a specific time corresponding with increases in expression of genes important for mature liver function, such as drug metabolizing enzymes. H19’s role in the regulation of liver maturation is currently unknown. Using an H19 knockout mouse model to determine the role of H19 in liver development, we quantified gene expression for insulin growth factor signaling, Wnt signaling, key cytochrome P450 (P450) enzymes known to change as the liver develops, and fetal and adult plasma protein produced in liver. In mice lacking H19 expression, liver weights were significantly increased immediately after birth and significant increases were found in the number of actively proliferating cells. Increases in cell proliferation may be due to increases in β-catenin protein affecting Wnt signaling, increases in insulin-like growth factor 2 (IGF2) expression, and/or increases in insulin-like growth factor 1 receptor (IGF1R) expression at the protein level. Loss of targeted inhibition of IGF1R by microRNA 675 (miR-675) may be the cause of IGF1R increases, as miR-675 expression is also abrogated with loss of H19 expression in our model. P450 expression patterns were significantly altered for certain P450 genes at particular time points in development, but were largely unchanged. No change in the production of plasma proteins was found, indicating H19 may not be important for liver maturation despite its role in controlling cell proliferation during liver growth. H19 may be important for normal liver development, and understanding how the liver matures will assist in predicting drug efficacy and toxicity in pediatric populations.

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