Contributor: Assoc Prof G.V. Shivashankar, MBI, Singapore Updated on: August 2012
Contribute | Nuclear MechanotransductionEukaryotic cells constantly sense their local microenvironment through surface mechanosensors for physical and soluble signals. Integration of these physicochemical cues by cells not only results in cytoskeletal modifications but also significantly impinges on the functional nuclear landscape and its mechanical properties. However, its physical properties such as morphology, position, stiffness and organization ought to be maintained for proper functioning of the cell. In this topic, we describe the various steps involved in transmission of environmental cues to the nucleus, how they affect the nuclear architecture and function leading to changes that elicit a response. We also discuss the interdependence of the cytoskeletal and nuclear mechanics in the process of adaptation to the constantly changing environment in order to maintain homeostasis at the cellular as well as systems level. Contents:Unit 1: Nuclear PrestressUnit 2: Higher order chromatin organization and transcription Unit 3: Nuclear mechanosignaling pathways Unit 4: Nuclear mechanics in differentiation and diseases Unit 5: Modeling nuclear mechanics: active stresses, polymers and signaling ————————————–
An overviewAs an integral part of cellular behavior, cells are sensitive to matrix rigidity, local geometry and stress or strain applied by external factors [1]. In recent years, it has been established that an extensive network of protein assembly couples the cytoskeleton to the nucleus [2] (reviewed in [3]) and that condensation forces of the chromatin balance cytoskeletal forces resulting in a prestressed nuclear organization [4, 5]. Thence, besides remodeling cytoskeletal filaments, the forces generated within the cell and that experienced at distant cell surface sites converge to the nucleus. This can happen either by physical transmission along the linked cytoskeleton [6] (reviewed in [3]) or by chemical signaling, where transcription regulators get transported to the nucleus upon activation [7, 8] (reviewed in [9]). These mechanosignals have a significant impact on the mechanical properties of the nucleus such as shape and rigidity (reviewed in [6, 10]) through modification of the scaffolding proteins at the nuclear envelope and interior. The mechanical cues are sorted in a highly regulated manner leading to chemical modification of the DNA, nucleoskeletal proteins and histones [11]. The process encompasses reorganization of chromosomes and spatiotemporal assembly of dynamic transcription compartments at specific promoters, which often cluster at interchromosome territories in the 3D nuclear space and share transcription machinery [12, 13] (reviewed in [9, 14]). Thus combinatorial control of genes is achieved depending on the cellular context and nature of the external signal (reviewed in [15]). Therefore akin to the cytoskeleton, nucleus has also been demonstrated to act as a load bearing organelle that physically transmits mechanical cues [16] leading to altered gene expression patterns (reviewed in [17, 18]) and hence a plethora of cellular traits such as shape, motility, differentiation and development [19, 20, 21](reviewed in [22]). What properties of the nucleus make it a substrate for mechanotransduction?Similar to the concept of long distance force propagation along cytoskeleton based on the tensegrity model, the prestressed nuclear state due to intracellular force balance enables mechanotransduction [4, 23]. Both the nuclear envelope and nuclear interior contribute to its mechanical properties.Several studies on nuclear mechanical properties have convincingly established that the nucleus is about 3-10 times stiffer than the surrounding cytoplasm depending on cell type [24, 25]. Nuclear stiffness is mainly attributed to lamins A and C, that form a network underneath the nuclear envelope termed ‘nuclear lamina’ [26, 27]. Their role is very evident in the case of stem cells, where lamin A is absent. Hence their nuclei are highly fragile while upon differentiation (expression of lamin A) they stiffen and resist deformation [28]. Further, the plasticity of stem cell nucleus is attributed to enhanced collisions between chromosome interfaces due to lack of spatial organization. Differentiated cells reveal precise cell-type specific positional coordinates for each chromosome through physical anchoring to other chromosomes or scaffolding proteins [29, 30, 31, 32]. Such well-defined interfaces are brought about by the orderly assembly of nuclear structural proteins upon activation of gene expression programs [33, 34]. Microrheology studies have also demonstrated a higher viscoelastic modulus for the nucleoplasm relative to cytoplasm arising primarily due to the heterogeneous chromatin organization [35, 36, 37]. The nuclear envelope behaves like an elastic sac with gel-like viscous contents [38, 39]. Hence it can undergo reversible stiffening or softening and deformation depending on the nature and timescale of force experienced [39, 40, 41]. The importance of nuclear mechanics is reflected in many disease conditions as discussed here. |
