A genetic approach to study the role of nuclear envelope components in nuclear positioning

In many cell types, the nucleus is positioned to a specific location. Our work and that of others has demonstrated that several integral nuclear envelope proteins function to move the nucleus and to anchor it in place. Our forward genetics approach has identified three components of the nuclear envelope involved in nuclear positioning. ANC-1 consists of two actin-binding calponin domains, a huge central coiled domain, and a nuclear envelope targeting a domain termed the KASH domain. ANC-1 functions to physically tether the actin cytoskeleton to the outer nuclear membrane. UNC-83 is a novel protein that functions in an unknown manner during nuclear migration. UNC-83 contains a domain with weak homology to the KASH domain of ANC-1. UNC-84 is a SUN protein that is required for both nuclear migration and anchorage. UNC-84 recruits both UNC-83 and ANC-1 to the nuclear envelope. We propose a model where UNC-84 is an integral component of the inner nuclear membrane, with its SUN domain in the perinuclear space. The SUN domain then recruits ANC-1 and UNC-83, through interactions with their KASH domains, to the outer nuclear envelope. Together these proteins function to bridge the two membranes of the nuclear envelope, connecting the nuclear matrix to the cytoskeleton.