Laminopathies and A-type lamin-associated signalling pathways.

The nuclear envelope (NE) is the most important border in the eukaryotic cells, essential in maintaining the identity of the nuclear and cytoplasmic compartments and in allowing additional levels of regulation and control of the gene expression. Previous studies of our group provided new insights in the complex mechanisms that are involved in the pathogenesis of a group of human diseases, collectively referred to as laminopathies (Maraldi et al., 2003, 2004). In particular, we investigated the influences of disease-causing mutations in A-type lamins on the nuclear morphology and chromatin arrangement (Maraldi et al., 2005, 2006), on the involvement of prelamin A accumulation in progeric laminopathies (Maraldi and Lattanzi, 2007; Maraldi et al., 2007), and on the possible effects of altered lamin A forms on the availability of specific transcription factors (Maraldi et al., 2008. The outer and inner nuclear membranes (ONM and INM, respectively) are characterized by different sets of proteins; in fact, whilst most of the ONM proteins are likely to perform endoplasmic reticulumrelated functions, the roles of INM proteins depend on their interactions with a variety of nuclear proteins, which include lamins, nesprins and chromatin-associated proteins. The INM is associated with two types of lamins, lamin B and lamin A/C, which form the network of filaments of the nuclear lamina. The interactions of many INM proteins with lamins are essential to maintain the stability of the NE. On the other hand, the correct positioning of the nucleus within each cell type is mediated by interaction of nesprins, that span the NE lumen and interact with cytoskeletal elements, and SUNs that interact with the nuclear lamina. Specific interactions of INM proteins and lamins with chromatinassociated proteins are conceivably involved in the organization of the chromatin arrangement. Additional putative functions of the INM proteins and lamins, which are emerging from recent insights, include specific interactions with transcription factors, and modulation of signal transduction pathways. This issue is more than just academic, because defects in lamin and INM protein expression are linked to several human genetic diseases, whose pathogenic mechanisms can be elucidated taking into account the complex functional roles of the NE. Here we discuss the experimental evidence that reveal that the NE functions as a signalling node with an active role in mechanotransduction and suggest a more direct role in gene regulation than previously anticipated.