Primary Cilia, Ciliogenesis and the Actin Cytoskeleton: A Little Less Resorption, A Little More Actin Please

Abstract

Primary cilia are microtubule-based organelles that extend from the apical surface of most mammalian cells, forming when the basal body (derived from the mother centriole) docks at the apical cell membrane. They act as universal cellular “antennae” in vertebrates that receive and integrate mechanical and chemical signals from the extracellular environment, serving diverse roles in chemo-, mechano- and photo-sensation that control developmental signaling, cell polarity and cell proliferation. Mutations in ciliary genes cause a major group of inherited developmental disorders called ciliopathies. There are very few preventative treatments or new therapeutic interventions that modify disease progression or the long-term outlook of patients with these conditions. Recent work has identified at least four distinct but interrelated cellular processes that regulate cilia formation and maintenance, comprising the cell cycle, cellular proteostasis, signaling pathways and structural influences of the actin cytoskeleton. The actin cytoskeleton is composed of microfilaments that are formed from filamentous (F) polymers of globular G-actin subunits. Actin filaments are organized into bundles and networks, and are attached to the cell membrane, by diverse cross-linking proteins. During cell migration, actin filament bundles form either radially at the leading edge or as axial stress fibers. Early studies demonstrated that loss-of-function mutations in ciliopathy genes increased stress fiber formation and impaired ciliogenesis whereas pharmacological inhibition of actin polymerization promoted ciliogenesis. These studies suggest that polymerization of the actin cytoskeleton, F-actin branching and the formation of stress fibers all inhibit primary cilium formation, whereas depolymerization or depletion of actin enhance ciliogenesis. Here, we review the mechanistic basis for these effects on ciliogenesis, which comprise several cellular processes acting in concert at different timescales. Actin polymerization is both a physical barrier to both cilia-targeted vesicle transport and to the membrane remodeling required for ciliogenesis. In contrast, actin may cause cilia loss by localizing disassembly factors at the ciliary base, and F-actin branching may itself activate the YAP/TAZ pathway to promote cilia disassembly. The fundamental role of actin polymerization in the control of ciliogenesis may present potential new targets for disease-modifying therapeutic approaches in treating ciliopathies.

Immunolocalization studies of vimentin and ACE2 on the surface of cells exposed to SARS-CoV-2 Spike proteins

“…Although additional studies in primary cells and tissue specimens need to be carried out to confirm these results, vimentin also seems to coincide with the signal of acetylated tubulin in images from primary rat cardiac fibroblasts and human tissue depicted in a recent report [56]. Some previously known connections between intermediate filaments and primary cilium include the regulatory role of several intermediate filament-associated proteins, including trichoplein and filamin A in ciliogenesis [79,80], as well as the presence of a net of intermediate filaments around basal bodies [81]. Nevertheless, to the best of our knowledge, the participation of vimentin in cilium architecture had not been underscored.…”

Primary Cilia in Glial Cells: An Oasis in the Journey to Overcoming Neurodegenerative Diseases

“…In addition, SOD1 (G93A) mutant mice showed increased expression of several Wnt signaling-related genes, including both canonical and non-canonical Wnts in the spinal cord ( Yu et al, 2013 ; Table 1 ). ACTIN-mediated cellular dynamics is important not only for neuronal function but also for ciliary formation and function ( Smith et al, 2020 ), and Wnt signaling is important for initiating myelination ( Tawk et al, 2011 ) and controlling ciliary formation and function ( Lee, 2020 ). Accordingly, studies determining whether primary cilia in Schwann cells are involved in the pathological mechanism of ALS through the regulation of Wnt signaling or ACTIN-mediated cellular function would be of interest.…”

Myocardin-related transcription factor and serum response factor regulate cilium turnover by both transcriptional and local mechanisms

“…Indeed, the state of the cytoskeleton has been recognized as a major determinant of PC assembly and disassembly, in that subtly regulated actin dynamics is central for both ciliogenesis and PC resorption (Copeland, 2020;Copeland et al, 2018). Excessive actin polymerization (Drummond et al, 2018;Hernandez-Hernandez et al, 2013;Pitaval et al, 2010;Smith et al, 2020), myosin contractility (Pitaval et al, 2010;Rozycki et al, 2014) and activation of RhoA or Rho kinase (Hernandez-Hernandez et al, 2013;Rangel et al, 2019;Stewart et al, 2016) suppress ciliogenesis or restrict PC growth. Moreover, evidence is accumulating that ciliation is controlled by local Rho activity and cytoskeleton organization.…”