In many cell types, including any polarized cell, the nucleus is positioned to a specific location. This is accomplished by two related processes: nuclear migration through the cytoplasm and anchorage of the nucleus to its proper position. Defects in nuclear envelope components and nuclear migration machinery lead to a variety of diseases including muscular dystrophy and lissencephaly. Despite the developmental importance of nuclear positioning, little is understood about how it is controlled.
Our work has demonstrated that several integral nuclear envelope proteins function to move the nucleus and to anchor it in place. Our forward genetic approach in C. elegans has identified three conserved components of the nuclear envelope involved in nuclear positioning. ANC-1 functions to physically tether the actin cytoskeleton to the outer nuclear membrane. UNC-83 is a novel protein that functions to target and regulate microtubule motors to the nucleus during nuclear migration. UNC-83 and ANC-1 both contain KASH domains, which target them to the outer nuclear membrane. 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. We are currently testing this nuclear envelope bridging model by a variety of molecular genetic and biochemical techniques.