Evaluating Effects of Hypomorphic Thoc1 Alleles on Embryonic Development in Rb1 Null Mice

Abstract

The Rb1 tumor suppressor protein is a molecular adaptor, physically linking transcription factors like E2f with various proteins acting on DNA or RNA to repress gene expression. Loss of Rb1 liberates E2f to activate the expression of genes mediating resulting phenotypes. Most Rb1 binding proteins, including E2f, interact through carboxyl-terminal protein interaction domains, but genetic evidence suggests an amino-terminal protein interaction domain is also important. One protein which binds Rb1 through the amino-terminal domain is encoded by Thoc1, a required component of the THO ribonucleoprotein complex important for RNA processing and transport. The physiological relevance of this interaction is unknown. Here we test whether Thoc1 mediates effects of Rb1 loss on mouse embryonic development. We find Thoc1 deficiency delays embryo lethality, and this delay correlates with reduced apoptosis in the brain. E2f protein levels are reduced in Rb1:Thoc1 deficient brain tissue. Expression of apoptotic regulatory genes regulated by E2f, like Apaf1 and Bak1, are also reduced. These observations suggest Thoc1 is required to support increased expression of E2f and apoptotic regulatory genes which trigger apoptosis upon Rb1 loss. These findings implicate Rb1 in the regulation of the THO ribonucleoprotein complex.