Chatterji, S. | Search bioRxiv

bioRxiv2024

The Diversified Astrocyte Developmental Programs are Modulated by Primary Ciliary Signaling

Astrocyte diversity is greatly influenced by local environmental modulation. Here, we report that the vast majority of brain astrocytes across the entire brain possess a singular primary cilium, a specialized signaling antenna localized to cell soma. Comparative single-cell transcriptomics reveals that primary cilia mediate canonical Shh signaling to modulate astrocyte subtype-specific core features in synaptic regulation, intracellular transport, energy and metabolism. Independent of canonical Shh signaling, primary cilia are important regulators for astrocyte morphology and intracellular signaling balance. Dendritic spine analysis and transcriptomics reveal that perturbation of astrocytic cilia leads to disruption of neuronal development and global intercellular connectomes in the brain. Ultimately, mice with primary ciliary deficient astrocytes show behavioral deficits in sensorimotor function, sociability, learning and memory. Our results uncover a critical role for primary cilia in transmitting local cues that drive the region-specific diversification of astrocytes within the developing brain.

neuroscience↗

bioRxiv2020

Epithelial Cell-like Elasticity Modulates E-cadherin Adhesion Organization

E-cadherin adhesions are essential for cell-to-cell cohesion and mechanical coupling between epithelial cells and reside in a micro-environment that comprises the adjoining epithelial cells. While E-cadherin has been shown to be a mechanosensor, it is unknown if E-cadherin adhesions can differentially sense stiffness within the range of that of epithelial cells. A survey of literature shows that epithelial cells Youngs moduli of elasticity lie predominantly in the sub kPa to few kPa range, with cancer cells often being softer than non-cancerous ones. Here, we devised oriented E-cadherin-coated soft silicone substrates with sub kPa or few kPa elasticity, but with similar viscous moduli, and found that E-cadherin adhesions differentially organize depending on the magnitude of epithelial cell-like elasticity. Linearly shaped E-cadherin adhesions associated with radially oriented actin, but not irregularly shaped E-cadherin adhesions associated with circumferential actin foci, were much more numerous on 2.4 kPa E-cadherin substrates compared to 0.3 kPa E-cadherin substrates. However, the total amount of E-cadherin in both types of adhesions taken together was similar on the 0.3 kPa and 2.4 kPa E-cadherin substrates, across many cells. Furthermore, while the average extent of nuclear recruitment of the mechanoresponsive transcription factor YAP on the 0.3 kPa E-cadherin substrate was undiminished relative to that on the 2.4 kPa substrate, a fraction of cells on the softer substrate displayed relatively high levels of YAP nuclear recruitment. Our results show that E-cadherin adhesions can be regulated by epithelial cell-like elasticity and have significant implications for disease states like carcinomas characterized by altered epithelial cell elasticity.

biophysics↗