Regulation of Neuronal Differentiation by Proteins Associated with Nuclear Bodies

Abstract

Nuclear bodies are large sub-nuclear structures composed of RNA and protein molecules. The Survival of Motor Neuron (SMN) protein localizes to Cajal bodies (CBs) and nuclear gems. Diminished cellular concentration of SMN is associated with the neurodegenerative disease Spinal Muscular Atrophy (SMA). How nuclear body architecture and its structural components influence neuronal differentiation remains elusive. In this study, we analyzed the effects of SMN and two of its interaction partners in cellular models of neuronal differentiation. The nuclear 23 kDa isoform of Fibroblast Growth Factor – 2 (FGF-223) is one of these interacting proteins – and was previously observed to influence nuclear bodies by destabilizing nuclear gems and mobilizing SMN from Cajal bodies (CBs). Here we demonstrate that FGF-223 blocks SMN-promoted neurite outgrowth, and also show that SMN disrupts FGF-223-dependent transcription. Our results indicate that FGF-223 and SMN form an inactive complex that interferes with neuronal differentiation by mutually antagonizing nuclear functions. Coilin is another nuclear SMN binding partner and a marker protein for Cajal bodies (CBs). In addition, coilin is essential for CB function in maturation of small nuclear ribonucleoprotein particles (snRNPs). The role of coilin outside of Cajal bodies and its putative impacts in tissue differentiation are poorly defined. The present study shows that protein levels of nucleoplasmic coilin outside of CBs decrease during neuronal differentiation. Overexpression of coilin has an inhibitory effect on neurite outgrowth. Furthermore, we find that nucleoplasmic coilin inhibits neurite outgrowth independent of SMN binding revealing a new function for coilin in neuronal differentiation.

Specific genomic cues regulate Cajal body assembly

“…The presence of CBs in neuronal cells, including terminally differentiated neurons that are incapable of cell division, is potentially indicative of a lineage-specific factor that positively or negatively regulates CB component oligomerization, such as neuronal growth factor (NGF) or fibroblast growth factor (FGF). 130,131 Alternatively the appearance of CBs in these cells is part of a metabolic response. Specifically, the presence of CBs in brain tissue could be a cellular response to high splicing demands, as neuronal tissues have among the highest rates of alternative splicing in humans.…”

Coalition of Nuclear Receptors in the Nervous System

“…However, several aspects of nuclear organization still remain a conundrum. For example, the dynamic architecture of the nucleus including regulatory positioning of chromosomes and specific functions of large, endogenous aggregates (nuclear bodies) has been revealed only recently (Hebert, ; Förthmann et al, , 2015). Moreover, some non‐canonical proteins have been identified in the nucleus and their functional role characterized.…”

Coilin mediates m6A RNA methylation through phosphorylation of METTL3

“…However, many noncanonical functions have been described for coilin. Some of these functions include a role in the DNA damage response ( Velma et al, 2010 , 2012 ; Bartova et al, 2014 ), neuronal differentiation ( Krejci et al, 2017 ; Forthmann et al, 2013 ), and the viral response ( Shaw et al, 2014 ; Shaw et al, 2019 ; Makhotenko et al, 2019 ). In wanting to understand how coilin might participate in miRNA biogenesis, our lab has investigated coilin's interaction with the microprocessor complex.…”