Syndecan-4 mediates the cellular entry of adeno-associated virus 9

Due to their low pathogenicity, immunogenicity, and long-term gene expression, adeno-associated virus (AAV) vectors emerged as safe and efficient gene delivery tools, over-coming setbacks experienced with other viral gene delivery systems in early gene therapy trials. Among AAVs, AAV9 can translocate through the blood-brain barrier (BBB), making it a promising gene delivery tool for transducing the central nervous system (CNS) via systemic administration. Recent reports on the shortcomings of AAV9-mediated gene delivery into the CNS require reviewing the molecular base of AAV9 cellular biology. A more detailed understanding of AAV9’s cellular entry would eradicate current hurdles and enable more efficient AAV9-based gene therapy approaches. Syndecans, the transmembrane family of heparan-sulfate proteoglycans, facilitate the cellular uptake of various viruses and drug delivery systems. Utilizing human cell lines and syndecan-specific cellular assays, we assessed the involvement of syndecans in AAV9’s cellular entry. The ubiquitously expressed isoform, syndecan-4 proved its superiority in facilitating AAV9 internalization among syndecans. Introducing syndecan-4 into poorly transducible cell lines enabled robust AAV9-dependent gene transduction, while its knockdown reduced AAV9’s cellular entry. Attachment of AAV9 to syndecan-4 is mediated not just by the polyanionic heparan-sulfate chains but also by the cell-binding domain of the extracellular syndecan-4 core protein. Co-immunoprecipitation assays and affinity proteomics also confirmed the role of syndecan-4 in the cellular entry of AAV9. Overall, our findings highlight the universally expressed syndecan-4 as a significant contributor to the cellular internalization of AAV9 and provide a molecular-based, rational explanation for the low gene delivery potential of AAV9 into the CNS

The ins and outs of the plant cell cycle

Plant growth and development are driven by the continuous generation of new cells. Whereas much has been learned at a molecular level about the mechanisms that orchestrate progression through the different cell-cycle phases, little is known about how the cell-cycle machinery operates in the context of an entire plant and contributes to growth, cell differentiation and the formation of new tissues and organs. Here, we discuss how intrinsic developmental signals and environmental cues affect cell-cycle entry and exit

The interplay between auxin and the cell cycle during plant development

The essential role of auxin for cell proliferation in plants is well known. Both auxin signaling and cell cycle regulation have been studied elaborately, but less is known about the connection between these processes. Recent studies report on the first molecular pathways that have been found to directly link auxin levels to the regulation of cell cycle activity. Here, we discuss the general effect of auxin on cell cycle progression and then zoom in on the interplay between auxin and the cell cycle during root development in Arabidopsis thaliana. At the root tip, an auxin gradient maintains the correct organization of the ground tissue layers and controls the size of the root apical meristem. During auxin-induced lateral root initiation LATERAL ORGAN BOUNDARIES-DOMAIN transcription factors are upregulated and control reactivation of the cell cycle and cell specification, both of which are needed for proper lateral root initiation. Auxin-induced lateral root initiation-like pathways are also involved in cell cycle reactivation during the formation of nematode feeding sites, nitrogen-fixing nodules and callus tissue, pointing to the existence of one common auxin–cell cycle module to initiate new organs in plants