Date of Award

8-2007

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Genetics

Advisor

Srivastava, Anand K

Committee Member

Abbott , Albert

Committee Member

Chen , Chin-Fu

Committee Member

Dupont , Barbara

Committee Member

Morris , James

Abstract

The mammalian brain expresses two angiotensin II specific receptors, the angiotensin II type 1 (AGTR1) and type 2 (AGTR2). Studies in humans and mice indicate a possible role for AGTR2 in learning, memory and behavior. However, AGTR2 gene function in the brain, and the molecular mechanisms by which AGTR2 exerts its physiological action, remains elusive. This study examines the possible role of AGTR2 in the developing brain and in brain function by employing three different approaches.
To identify genes in the developing brain that depend on AGTR2 function, a microarray analysis was conducted that compared the gene expression of Agtr2-/y mouse brains to normal controls at embryonic day 15 and postnatal day 1. Genes involved in microtubule regulation, cell adhesion and glutamate metabolism were found to be up-regulated in Agtr2-/y mouse brains. These results suggest that AGTR2 may contribute to the developing brain by influencing cell morphology and synaptic connectivity.
Using a yeast two-hybrid system, the amino-terminal extracellular domain and carboxy-terminal intracellular domain of AGTR2 were screened against a human fetal brain cDNA library to identify AGTR2 interacting proteins. Three novel AGTR2 interacting proteins, ASMTL, GNB2L1 and NGLY1 were identified.
Lastly, a brain-specific isoform of a previously identified AGTR2 interacting protein, ATIP, was explored as a potential candidate gene for mental retardation. Limited screening of the ATIP gene in 80 patients with mental retardation identified two non-pathogenic sequence variants but no disease causing mutations.
In summary, this study unveils several functional classes of genes as potential downstream targets of AGTR2 and identifies three new AGTR2 interacting proteins in the developing brain. Further functional studies of the newly identified AGTR2 interacting proteins and some of the genes influenced by AGTR2 may provide clues to AGTR2-mediated signaling in the developing brain and in brain function.

Included in

Genetics Commons

Share

COinS