Biology subjects

Kirkise, N.

Publications and source records attributed to Kirkise, N..

3 recordsLinked to original sources

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↗

bioRxiv2026

Laminin and BDNF synergistically induce local translation in axonal growth cones

AO_SCPLOWBSTRACTC_SCPLOWThe laminins are a family of extracellular matrix proteins that regulate numerous cellular processes, including adhesion, neurite outgrowth, and axon guidance. However, it remains unclear whether laminin regulates axon guidance through local translation. Here, we show that laminin is necessary for local translation in axonal growth cones. Local translation is significantly increased in growth cones of embryonic day 17 mouse cortical neurons, either cultured on or acutely stimulated with soluble laminin 111, in the presence of BDNF. When cultured on laminin isoforms 211 or 221 in the presence of BDNF, there was a remarkable decrease in local translation in growth cones. Using a puromycin-proximity ligation assay to examine newly synthesized {beta}-actin specifically, we find a significant increase in growth cones of neurons cultured on laminin 111 in the presence of BDNF. However, soluble laminin 111 alone results in a significant reduction in nascent {beta}-actin protein synthesis. These results indicate that laminin isoforms can act in multiple ways, including synergistically with guidance cues and independently, to modulate local mRNA translation, thereby differentially influencing axon growth and guidance during development. SO_SCPLOWUMMARYC_SCPLOW SO_SCPLOWTATEMENTC_SCPLOWLocal translation in axons is critical for axon guidance. Laminin, a key component of the extracellular matrix, is necessary to induce local translation and thus mediate axon growth and guidance.

neuroscience↗

bioRxiv2025

Restoring DSCAM expression rescues neuronal morphology and axon guidance deficits in Down syndrome

Down syndrome (DS) results from the triplication of human chromosome 21 (HSA21) and is the leading cause of intellectual disability. Down syndrome cell adhesion molecule (DSCAM) is located on HSA21 and is overproduced in DS. DSCAM is a receptor for netrin-1 and important for neural wiring in the developing brain. Using a Dscam gain-of-function mouse model and human induced pluripotent stem cell (hiPSC)-derived cortical neurons, in combination with cellular, molecular, and behavioral approaches, this study aims to understand how DSCAM triplication and its subsequent excessive production contribute to changes in neural development and intellectual disability in DS. Analysis of morphological parameters revealed impaired neuronal development and loss of netrin-1-mediated axon guidance in mouse hippocampal pyramidal neurons overexpressing DSCAM. Furthermore, DSCAM overexpression reduces interhemispheric connectivity in vivo, and hippocampal- dependent learning in adult mice. DS hiPSC-derived excitatory pyramidal neurons exhibit a similar phenotype: impaired morphological development and loss of netrin-1-mediated axon guidance. Remarkably, normalization of DSCAM in DS hiPSC-derived neurons rescues many of these neuronal phenotypes, including reduced axon length and deficits in axon guidance. These results suggest that DSCAM plays an essential role in the development of neurons and neuronal networks, and its overproduction contributes to intellectual disability in DS.

neuroscience↗