Intranuclear Actin Regulates Osteogenesis

Abstract

Depolymerization of the actin cytoskeleton induces nuclear trafficking of regulatory proteins and global effects on gene transcription. We here show that in mesenchymal stem cells (MSCs), cytochalasin D treatment causes rapid cofilin-/importin-9-dependent transfer of G-actin into the nucleus. The continued presence of intranuclear actin, which forms rod-like structures that stain with phalloidin, is associated with induction of robust expression of the osteogenic genes osterix and osteocalcin in a Runx2-dependent manner, and leads to acquisition of osteogenic phenotype. Adipogenic differentiation also occurs, but to a lesser degree. Intranuclear actin leads to nuclear export of Yes-associated protein (YAP); maintenance of nuclear YAP inhibits Runx2 initiation of osteogenesis. Injection of cytochalasin into the tibial marrow space of live mice results in abundant bone formation within the space of 1 week. In sum, increased intranuclear actin forces MSC into osteogenic lineage through controlling Runx2 activity; this process may be useful for clinical objectives of forming bone.

Persistent nuclear actin filaments inhibit transcription by RNA polymerase II

“…Nuclear actin polymerization has been implicated in cellular differentiation (Sen et al, 2015), DNA damage clearance (Belin et al, 2015) and adenoviral replication (Fuchsova et al, 2015). Transient actin filaments, detected in nuclei upon serum stimulation or cell spreading, are reported to regulate the MAL (also known as MRTF) transcription factor pathway (Baarlink et al, 2013;.…”

“…Nuclear actin filaments have also been noted following treatment with actin-depolymerizing drugs (Belin et al, 2013;Sen et al, 2015;Yahara et al, 1982) and upon dysregulation of actin-binding proteins such as exportin-6 (Dopie et al, 2015(Dopie et al, , 2012 and MICAL-2 (Lundquist et al, 2014). Furthermore, acute cellular stress, such as heat shock, as well as huntingtin mutations, lead to the formation of micron long actin and cofilin nuclear rods (Munsie et al, 2011;Nishida et al, 1987).…”

Proteome analysis of human serum proteins adsorbed onto different titanium surfaces used in dental implants

“…The identified proteins are presented in Table 1 gelsolin (Kwiatkowski et al 1989;Thouverey et al 2011;Kim et al 2013) and actin cytoplasmic 1 (Sen et al 2015). LCMS/MS analysis also revealed the cellular and secreted proteins associated with bone homeostasis, such as peptidyl-prolyl cis-trans isomerase B (Pyott et al 2011) and lysozyme C (Siebert et al 1978;Briggs & Arinzeh 2014).…”

Pathways Involved in Formation of Mammary Organoid Architecture Have Keys to Understanding Drug Resistance and to Discovery of Druggable Targets

“…Although polymeric actin is an essential cytoskeletal component in the cytosol, monomeric actin is shuttled between the cytosol and nucleus (Sen et al 2015). In the nucleus, actin plays critical roles in nuclear matrix organization, chromatin remodeling, mRNA processing, and transcriptional regulation (Visa and Percipalle 2010).…”

“…In the nucleus, actin plays critical roles in nuclear matrix organization, chromatin remodeling, mRNA processing, and transcriptional regulation (Visa and Percipalle 2010). Nuclear actin is part of the nuclear matrix (Kiseleva et al 2004) and interacts with the nuclear lamina, pre-mRNA splicing proteins, and chromatin remodeling complexes for transcriptional activation of tissue-specific genes (Clubb and Locke 1998;Lamond and Spector 2003;Gruenbaum et al 2005;Farrants 2008;Visa and Percipalle 2010;Sen et al 2015). Conversely, polymeric actin in the nucleus is thought to play roles in regulating nuclear shape and positioning in response to mechanical stress (Plessner et al 2015).…”