Bumbledare, T. | Search bioRxiv

bioRxiv2026

Cellular Morphology and Motility Defects are Conserved Phenotypes of Trisomy 21 Despite Heterogeneous Adhesion Mechanisms

Down syndrome is a neurodevelopmental disorder caused by the trisomy of human chromosome 21 (T21). Down syndrome is associated with a wide range of variable clinical features, including congenital heart defects and slow wound healing; however, intellectual disability is ubiquitous and results, in part, from altered neuronal connectivity. Here, we used three sets of control and T21 human fibroblasts, and one set of human induced pluripotent stem cell (hiPSC)-derived cortical neurons, to examine whether changes in cellular morphology and motility are consistent across cell types in Down syndrome and to elucidate the underlying mechanisms. We found that fibroblast morphology is dysregulated in all T21 fibroblast lines. Using a transwell migration assay, cellular migration is decreased in two of the three T21 fibroblast lines. T21 hiPSC-derived cortical neurons also exhibit morphological defects, including a decrease in the length of the longest neurite and growth cone area. Because of these significant changes in morphology and motility in T21 cells, we examined proteins in the focal adhesion complex, which links the intracellular cytoskeleton to the extracellular matrix and directly controls these processes. Multiple proteins in the adhesion complex, including paxillin, vinculin, talin, and RACK1, are dysregulated in T21 fibroblasts and hiPSC-derived neurons, but these changes have high inter-individual variability. Taken together, these findings suggest that altered cellular morphology and motility are conserved features of Down syndrome that arise through heterogeneous alterations in adhesion networks. Thus, this work significantly contributes to the recent literature highlighting the need for personalized medicine in Down syndrome.

cell biology↗

bioRxiv2019

RACK1 is required for axon guidance and local translation at growth cone point contacts

Local translation regulates the formation of appropriate connectivity in the developing nervous system. However, the localization and molecular mechanisms underlying this translation within growth cones is not well understood. Receptor for activated C kinase 1 (RACK1) is a multi-functional ribosomal scaffolding protein that interacts with {beta}-actin mRNA. We recently showed that RACK1 localizes to and regulates the formation of point contacts, which are adhesion sites that control growth cone motility. This suggests that local translation occurs at these adhesion sites that are important for axonal pathfinding, but this has not been investigated. Here, we show that RACK1 is required for BDNF-induced local translation of {beta}-actin mRNA in growth cones. Furthermore, the ribosomal binding function of RACK1 regulates point contact formation, and axon growth and guidance. We also find that local translation of {beta}-actin occurs at point contacts. Taken together, we show that adhesions are a targeted site of local translation within growth cones, and RACK1 is critical to the formation of point contacts and appropriate neural development. These data provide further insight into how and where local translation is regulated, and thereby leads to appropriate connectivity formation in the developing nervous system.

neuroscience↗