New roles for lamins, nuclear envelope proteins and actin in the nucleus

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Laminopathies and A-type lamin-associated signalling pathways

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At the nucleus of the problem: nuclear proteins and disease.

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Muscular laminopathies: Role of prelamin A in early steps of muscle differentiation.

Mutations in A-type lamins or lamin-binding proteins are involved in the pathogenesis of diseases referred to as laminopathies (Worman et al., 2009). They include both tissue-specific disorders affecting striated muscle (muscular laminopathies), adipose tissue (lipodystrophic laminopathies), and syndromes in which many tissues undergo premature ageing (progeric laminopathies). Howmutations in LMNA cause diverse diseases is one of the most intriguing riddle in medical genetics. Two hypotheses have emerged to account for the molecular basis of the wide spectrum of these diseases. The mechanical stress hypothesis, mainly based on observations in cultured cells, proposes that mutations in A-type lamins lead to increased nuclear fragility and eventual nuclear disruption in tissues exposed to mechanical strain (Lammerding et al., 2005). The gene expression hypothesis suggests that mutations in A-type lamins lead to abnormal tissue-specific gene regulation. This model is based on findings that A-type lamins and associated proteins bind to chromatin and transcriptional regulators. The gene expression hypothesis does not exclude effects that mechanical stress may have on cells; in fact, both gene expression, as well as signalling pathways and mechanical integrity should be perturbed in cells carrying laminopathy mutations (Cohen et al., 2008). Furthermore, signalling pathways that culminate in transcription factor activity may also be regulated at the nuclear envelope and lamina, which act as a platform or scaffold necessary for the appropriate localization of factors important in specific tissue differentiation (Schirmer and Foisner, 2007; Pekovic and Hutchison, 2008; Andr\ue9s and Gonzalez, 2009)

Mitigation of B1+ inhomogeneity using spatially selective excitation with jointly designed quadratic spatial encoding magnetic fields and RF shimming

The inhomogeneity of flip angle distribution is a major challenge impeding the application of high-field MRI. We report a method combining spatially selective excitation using generalized spatial encoding magnetic fields (SAGS) with radiofrequency (RF) shimming to achieve homogeneous excitation. This method can be an alternative approach to address the challenge of B1+ inhomogeneity using nonlinear gradients.We proposed a two-step algorithm that jointly optimizes the combination of nonlinear spatial encoding magnetic fields and the combination of multiple RF transmitter coils and then optimizes the locations, RF amplitudes, and phases of the spokes.Our results show that jointly designed SAGS and RF shimming can provide a more homogeneous flip angle distribution than using SAGS or RF shimming alone. Compared with RF shimming alone, our approach can reduce the relative standard deviation of flip angle by 56% and 52% using phantom and human head data, respectively.The jointly designed SAGS and RF shimming method can be used to achieve homogeneous flip angle distributions when fully parallel RF transmission is not available

Laminopathies: a chromatin affair

In the last 5 years, an impressive series of genetic diseases (16 distinct diseased phenotypes have been so far identified), affecting metabolic and/or developmental processes, have been demonstrated to be caused by mutation of LMNA gene and collectively referred to as laminopathies. Most of these diseases are characterized by dystrophic/degenerative processes affecting different tissues and organs. Nuclear defects, consisting in heterochromatin focal or total loss and in nuclear lamina thickening or invagination, characterize the cells from laminopathic patients. Furthermore, accumulation of pre-lamin A has been demonstrated to occur, at least in a large group of laminopathies. These findings suggest a possible pathogenic mechanism for laminopathies. The cells bearing mutated pre-lamin A could not be able to maintain the chromatin organization required by differentiation programs, which represents an epigenetic marker of each cell lineage undergoing a differentiation process. These alterations have been demonstrated to be due to a lack of mutant lamin A to physiologically interact with heterochromatin-associated proteins, including HP1. The use of specific drugs that interfere with the maturation of lamin A allowed us to demonstrate that the accumulation of farnesylated pre-lamin A induces the appearance of nuclear phenotypes similar to those occurring in progeric syndromes. Furthermore, LMNA mutations found in several laminopathies reduce the transcriptional capability of the cells accumulating pre-lamin A. Therefore, the pathogenic mechanism of laminopathies appears to involve alterations of the chromatin organization and transcriptional capability required by differentiation programs, not necessarily during early embryogenesis, in which cells lack lamin A/C, but in adult cell populations capable of differentiating under specific stimuli. These cells, that onstitute the stem reservoir of several adult tissues, and that are typically represented by mesenchymal stromal cells, in the presence of mutant lamin A/C, and of accumulating prelamin A, present phenotypic alterations of the chromatin pattern and impairment of gene expression mechanisms. This could result in an accelerated cellular senescence, which could be characterized by the presence of progerin in progeric laminopathies, and of pre-lamin A in other laminopathies, in which not all tissues but specific tissues are involved. In fact, lamins and lamin-associated proteins, by constituting a platform for the interaction with transcription factors, may contribute to a fine modulation of gene expression programs, typical of each cell lineage