Nuclear Lamins in the Brain — New Insights into Function and Regulation

Abstract

The nuclear lamina is an intermediate filament meshwork composed largely of four nuclear lamins—lamins A and C (A-type lamins) and lamins B1 and B2 (B-type lamins). Located immediately adjacent to the inner nuclear membrane, the nuclear lamina provides a structural scaffolding for the cell nucleus. It also interacts with both nuclear membrane proteins and the chromatin and is thought to participate in many important functions within the cell nucleus. Defects in A-type lamins cause cardiomyopathy, muscular dystrophy, peripheral neuropathy, lipodystrophy, and progeroid disorders. In contrast, the only bona fide link between the B-type lamins and human disease is a rare demyelinating disease of the central nervous system—adult-onset autosomal-dominant leukoencephalopathy, caused by a duplication of the gene for lamin B1. However, this leukoencephalopathy is not the only association between the brain and B-type nuclear lamins. Studies of conventional and tissue-specific knockout mice have demonstrated that B-type lamins play essential roles in neuronal migration in the developing brain and in neuronal survival. The importance of A-type lamin expression in the brain is unclear, but it is intriguing that the adult brain preferentially expresses lamin C rather than lamin A, very likely due to microRNA-mediated removal of prelamin A transcripts. Here, we review recent studies on nuclear lamins, focusing on the function and regulation of the nuclear lamins in the central nervous system.

Lamins regulate cell trafficking and lineage maturation of adult human hematopoietic cells

“…Although lamin-A,C splice-form ratios require further study, a major finding here is that lamin-B1 regulates lineage specification as well as nuclear stiffening. Consistent with wide variation in lamin A:B ratios between neuronal cell types (33) and between solid tissue cell types in general (34), our measurements of absolute stoichiometry demonstrate widely differing ratios of A-and B-type lamins in hematopoiesis, which might reflect selective cleavage of B-type lamins during early erythropoiesis (22) and general accumulation of lamins during MK polyploidization (35). One previous study of mouse embryonic fibroblasts suggested that lamin-B1 does not contribute to nuclear mechanics, but such cells could be dominated by lamin-A (36).…”

The nuclear lamina is mechano-responsive to ECM elasticity in mature tissue

“…LMNA transcription has been reported to be controlled by transcription factors of the retinoic-acid receptor family (RAR and RXR family proteins; Okumura et al, 2004a;Okumura et al, 2004b;Olins et al, 2001;Shin et al, 2013;Swift et al, 2013b), with the resulting mRNA alternatively spliced to give the lamin-A and truncated lamin-C forms. Soft tissue generally preferentially expresses the lamin-C spliceoform (Swift et al, 2013b), and, in brain, the micro-RNA MIR-9 specifically targets and deactivates the mRNA of the lamin-A spliceoform (Jung et al, 2012;Jung et al, 2013). Little is currently understood about different functional roles of lamin-A and lamin-C, although differences in both physical properties, such as mobility (Broers et al, 2005), and lamina assembly (Kolb et al, 2011;Pugh et al, 1997) have been reported.…”

“…elongation) that occurs during migration, perhaps explaining why the brain fails to develop in lamin-B-knockout mice (Coffinier et al, 2011;Jung et al, 2013;Kim et al, 2011). Neutrophilic cells also have very low levels of nucleoskeletal proteins to allow their deformation as they squeeze into confined spaces (Olins et al, 2009;Rowat et al, 2013), and indeed, the composition of the nuclear lamina is continuously regulated during hematopoiesis ( Fig.…”

The Cellular Mastermind(?)—Mechanotransduction and the Nucleus

“…14,64 A few specialized differentiated cells, notably neutrophils and neurons, hardly express any A-type lamins even after differentiation. 69,71 The lack of A-type lamins in embryonic stem cells, neutrophils, and neurons may facilitate migration, enabling these cells to travel through dense tissues and interstitial spaces during development and inflammation. 72 For example, the decrease in lamin A/C levels along with the concomitant increase in expression of lamin B receptor (LBR) during granulopoiesis promotes the distinct highly lobulated nuclear shape of mature neutrophils.…”