Undergraduate Honors Theses

Thesis Defended

Spring 2015

Document Type

Thesis

Type of Thesis

Departmental Honors

Department

Molecular, Cellular, & Developmental Biology

First Advisor

Harald Junge

Second Advisor

Ricardo Stephen

Third Advisor

Mike Klymkowsky

Fourth Advisor

Ravinder Singh

Abstract

The retina has the highest oxygen consumption rate of any tissue type within the body and thus, requires extensive vasculature to supply its needs. The blood vessels supplying this tissue form in a distinct and highly characterized manner, known to be under the control of the Norrin/Frizzled4 signaling pathway. Tetraspanin12 (TSPAN12), a membrane protein, is one of the proteins mediating this pathway, but its role in signaling initiation is largely unknown. I hypothesized that TSPAN12 may positively regulate Norrin/Frizzled4 signaling by promoting protein-protein interactions in the Norrin receptor complex. This study utilized the iDimerize system to survey the function of possible protein interactions among components of the Norrin receptor complex. The goal was to gain insight into which interactions promote signaling and to thereby help identify candidate interactions that may be promoted by TSPAN12. I show that forcing the interactions of Frizzled4 and the co-receptor LRP5 promotes two components of signaling: one is Norrin dependent signaling and the other component is Norrin independent. A point mutation in Frizzled4, M105V, impairs only the Norrin-dependent component of signaling and is rescued by TSPAN12. Along with other evidence, this suggests that TSPAN12 may rescue signaling defects of Frizzled4 M105V by promoting Norrin binding to Frizzled4.

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