The nuclear envelope links the cytoskeleton to structural components of the nucleus. It functions to coordinate nuclear migration and anchorage, organize chromatin, and aid meiotic chromosome pairing. Forces generated by the cytoskeleton are transferred across the nuclear envelope to the nuclear lamina through a nuclear-envelope bridge consisting of SUN (Sad1 and UNC-84) and KASH (Klarsicht, ANC-1 and Syne/Nesprin homology) proteins. Some KASH-SUN combinations connect microtubules, centrosomes, actin filaments, or intermediate filaments to the surface of the nucleus. Other combinations are used in cell cycle control, nuclear import, or apoptosis. Interactions between the cytoskeleton and the nucleus also affect global cytoskeleton organization. SUN and KASH proteins were identified through genetic screens for mispositioned nuclei in model organisms. Knockouts of SUN or KASH proteins disrupt neurological and muscular development in mice. Defects in SUN and KASH proteins have been linked to human diseases including muscular dystrophy, ataxia, progeria, lissencephaly, and cancer.

SUMMARY High-content screening for gene profiling has generally been limited to single cells. Here, we explore an alternative approach—profiling gene function by analyzing effects of gene knockdowns on the architecture of a complex tissue in a multicellular organism. We profile 554 essential C. elegans genes by imaging gonad architecture and scoring 94 phenotypic features. To generate a reference for evaluating methods for network construction, genes were manually partitioned into 102 phenotypic classes, predicting functions for uncharacterized genes across diverse cellular processes. Using this classification as a benchmark, we developed a robust computational method for constructing gene networks from high-content profiles based on a network context-dependent measure that ranks the significance of links between genes. Our analysis reveals that multi-parametric profiling in a complex tissue yields functional maps with a resolution similar to genetic interaction-based profiling in unicellular eukaryotes—pinpointing subunits of macromolecular complexes and components functioning in common cellular processes.

Caveolae, flask-like invaginations of the plasma membrane, were discovered nearly 60 years ago. Originally regarded as fixation artifacts of electron microscopy, the functional role for these structures has taken decades to unravel. The discovery of the caveolin protein in 1992 (by the late Richard G.W. Anderson) accelerated progress in defining the contribution of caveolae to cellular physiology and pathophysiology. The three isoforms of caveolin (caveolin-1, -2, and -3) are caveolae-resident structural and scaffolding proteins that are critical for the formation of caveolae and their localization of signaling entities. A PubMed search for "caveolae" reveals ∼280 publications from their discovery in the 1950s to the early 1990s, whereas a search for "caveolae or caveolin" after 1990, identifies ∼7000 entries. Most work on the regulation of biological responses by caveolae and caveolin since 1990 has focused on caveolae as plasma membrane microdomains and the function of caveolin proteins at the plasma membrane. By contrast, our recent work and that of others has explored the localization of caveolins in multiple cellular membrane compartments and in the regulation of intracellular signaling. Cellular organelles that contain caveolin include mitochondria, nuclei and the endoplasmic reticulum. Such intracellular localization allows for a complexity of responses to extracellular stimuli by caveolin and the possibility of novel organelle-targeted therapeutics. This review focuses on the impact of intracellular localization of caveolin on signal transduction and cell regulation.

The molecular motors kinesin-1 dynein navigate migrating nuclei around cytoplasmic roadblocks.