Diverse Roles of the LINC Complex in Cellular Function and Disease in the Nervous System

Abstract

The linker of nucleoskeleton and cytoskeleton (LINC) complex, which spans the nuclear envelope, physically connects nuclear components to the cytoskeleton and plays a pivotal role in various cellular processes, including nuclear positioning, cell migration, and chromosomal configuration. Studies have revealed that the LINC complex is essential for different aspects of the nervous system, particularly during development. The significance of the LINC complex in neural lineage cells is further corroborated by the fact that mutations in genes associated with the LINC complex have been implicated in several neurological diseases, including neurodegenerative and psychiatric disorders. In this review, we aimed to summarize the expanding knowledge of LINC complex-related neuronal functions and associated neurological diseases.

Keywords: LINC complex; cytoskeleton; diseases; nervous system; nuclear envelope.

Figure 1

The LINC complex connecting the cytoskeleton and nuclear component. The LINC complex comprises SUN proteins in the inner nuclear membrane (INM) and KASH proteins (Nesprin in mammals) in the outer nuclear membrane (ONM). The interaction between the SUN domain of SUN proteins and the KASH domain of KASH proteins in the lumen of the nuclear envelope (NE) forms a LINC complex that physically connects the cytoskeleton and nucleoskeleton. The nucleoplasmic domain of SUN proteins is associated with the nuclear lamina, anchoring chromatin beneath the INM. On the cytoplasmic side, ONM-penetrating KASH proteins possess a long spectrin repeat structure and interact with actin filaments through the calponin homology (CH) domain and with microtubules via motor proteins, such as dynein and kinesin.

Figure 2

Diverse cellular functions of the LINC complex. (A) Nuclear structure. The LINC complex is essential for the maintenance of nuclear shape and size and for nuclear dynamics during migration, and dysfunction of the LINC complex leads to severe abnormalities in nuclear size and nuclear envelope (NE) structure. (B) Mechanotransduction. The LINC complex transmits mechanical forces from the external environment to the nucleus through the cytoskeletal network. (C) Cytoskeletal regulation. The LINC complex tethers the centrosome to the nuclear envelope via microtubules to establish the centrosome–nucleus coupling, which is important for nuclear dynamics. The LINC complex also controls the formation of perinuclear actin stress fibers involved in mechanotransduction, such as actin caps and TAN line. (D) Nuclear positioning. In particular cells, the LINC complex determines and maintains specific nuclear positioning via motor proteins that move on the cytoskeleton. (E) Nuclear migration. Proper nuclear migration during the interkinetic nuclear migration (IKNM) and neuronal migration is essential for the construction of elaborative brain structures. The LINC complex and motor proteins cooperate to move the nucleus. The red and black arrows indicate the direction of nuclear migration and cell migration, respectively. (F) Chromatin configuration. Chromatin is spatially arranged in a nonrandom fashion, with heterochromatin at the nuclear periphery and euchromatin farther from the nuclear envelope. Since the LINC complex tethers chromatin to the nuclear envelope via nuclear lamina, defects in the LINC complex have a major impact on chromatin configuration and, thus, global gene expression.

Figure 3

The LINC complex-mediated regulation in the nervous system. (A) Nuclear positioning in cone photoreceptor cell. In wild-type, the cone nuclei are located at the most apical part of the outer nuclear layer (ONL). SUN1 or Nesprin-2 knockout (KO) results in abnormal basal positioning of the cone nuclei, thereby reducing the ONL thickness. (B) Nuclear positioning in muscle cell. The cluster of synaptic nuclei beneath the neuromuscular junction (NMJ) is abolished in Nesprin-1-deficient muscle cells. In addition, loss of Nesprin-1 results in clusters or arrays of nonsynaptic nuclei that are uniformly distributed in wild-type. (C) Nuclear positioning in outer hair cell (OHC). The OHC nuclei in wild-type are located on the most basal side; whereas, Nesprin-4 or SUN1 knockout OHC nuclei are abnormally located on the apical side. (D) Nuclear migration. Interkinetic nuclear migration (IKNM) is a cell-cycle-dependent dynamic nuclear migration between the apical and basal surfaces of neural progenitor cells in the neuroepithelium. In SUN1/2 double knockout (dKO) or Nesprin-2 knockout mice, the nuclei are not located on the apical surface in M-phase due to IKNM abnormalities. (E) Nuclear migration during neuronal migration. In newly born neurons, the motor protein adaptor BicD2 mediates the interaction of Nesprin-2 to either dynein or kinesin-1. Dynein moves the nucleus toward the centrosome side, the direction of cell advance (the pink arrows), while kinesin-1 pulls the nucleus in the opposite direction to dynein (blue arrow). The cooperative action of dynein and kinesin-1 may fine-tune the velocity of nuclear migration. The centrosome is depicted as a small blue circle in the schematic diagram of a neuron. (F) Synaptic function. Msp300, a Drosophila orthologue of Nesprin-1, contributes to synaptic maturation at the NMJ through multiple mechanisms. Msp300 with F-actin forms a long filamentous bridge between the nucleus and the nascent postsynaptic site at the NMJ. Through this “bridge”, Msp300 is involved in the transport of synaptic mRNAs to the postsynaptic sites, where those mRNAs undergo local translation. Msp300 itself is also locally translated in a neural activity-dependent manner at the postsynaptic site to form a postsynaptic actin scaffold network that is required for glutamate receptor anchoring. (G) Nuclear export. In choroid plexus cells, SUN1 captures OTX2 transcription factor at the nuclear periphery to initiate nuclear export of OTX2. Then, OTX2 is transported to the cytoplasm through the scission of nuclear budding vesicles mediated by TOR1A, which is localized in the nuclear envelope (NE) lumen followed by extracellular secretion. OTX2 secreted from choroid plexus cells reaches parvalbumin (PV) neurons in the developing visual cortex via cerebrospinal fluid (CSF) and plays an essential role in establishing visual function.