Biology subjects

Vandensteen, J.

Publications and source records attributed to Vandensteen, J..

3 recordsLinked to original sources

bioRxiv2025

A dynamic gene regulatory code drives synaptic development of hippocampal granule cells

Connecting neurons into functional circuits requires the formation, maturation, and plasticity of synapses. While advances have been made in identifying individual genes regulating synapse development, the molecular programs orchestrating their action during circuit integration of neurons remain poorly understood. Here, we take a multiomic approach to reconstruct gene regulatory networks (GRNs), comprising transcription factors (TFs), regulatory regions, and predicted target genes, in hippocampal granule cells (GCs). We find a dynamic gene regulatory code, with early and late postnatal GRNs regulating cell morphogenesis and synapse organization and plasticity, respectively. Our results predict sequential regulations, with early-active TFs delaying the activation of later GRNs and their putative synaptic targets. Using a loss-of-function approach, we identify Bcl6 as a regulator of pre- and postsynaptic structural maturation, and Smad3 as a modulator of inhibitory synaptic transmission, in GCs. Together, these findings highlight the networks of key TFs and target genes orchestrating GC synapse development.

neuroscience↗

bioRxiv2024

Decoupling shear stress and pressure effects in the biomechanics of autosomal dominant polycystic kidney disease using a perfused kidney-on-chip.

Kidney tubular cells are submitted to two distinct mechanical forces generated by the urine flow: shear stress and hydrostatic pressure. In addition, the mechanical properties of the surrounding extracellular matrix modulate tubule deformation under constraints. These mechanical factors likely play a role in the pathophysiology of kidney diseases as exemplified by autosomal dominant polycystic kidney disease, in which pressure, flow and matrix stiffness have been proposed to modulate the cystic dilation of tubules with PKD1 mutations. The lack of in vitro systems recapitulating the mechanical environment of kidney tubules impedes our ability to dissect the role of these mechanical factors. Here we describe a perfused kidney-on-chip with tunable extracellular matrix mechanical properties and hydrodynamic constraints, that allows a decoupling of shear stress and flow. We used this system to dissect how these mechanical cues affect Pkd1-/- tubule dilation. Our results show two distinct mechanisms leading to tubular dilation. For PCT cells (proximal tubule), overproliferation mechanically leads to tubular dilation, regardless of the mechanical context. For mIMCD-3 cells (collecting duct), tube dilation is associated with a squamous cell morphology but not with overproliferation and is highly sensitive to extracellular matrix properties and hydrodynamic constraints. Surprisingly, flow alone suppressed Pkd1-/- mIMCD-3 tubule dilation observed in static conditions, while the addition of luminal pressure restored it. Our in vitro model emulating nephron geometrical and mechanical organization sheds light on the roles of mechanical constraints in ADPKD and demonstrates the importance of controlling intraluminal pressure in kidney tubule models.

biophysics↗

bioRxiv2024

Cell-surface receptor-mediated regulation of synaptic organelle distribution controls dendritic spine maturation

The spine apparatus (SA), an endoplasmic reticulum-related organelle present in a subset of mature dendritic spines, plays a key role in postsynaptic development and has been implicated in various neurological disorders. However, the molecular mechanisms that dictate SA localization at selected synapses remain elusive. Here, we identify a postsynaptic signaling complex comprising the GPCR-like receptor GPR158 and a largely uncharacterized phospholipase C (PLC), PLCXD2, that controls SA abundance. Sparse genetic manipulations in vivo demonstrate that in the absence of GPR158, unrestrained PLCXD2 activity impedes postsynaptic SA incorporation and hampers dendritic spine maturation. Finally, we show that extracellular heparan sulfate proteoglycan (HSPG) binding modulates the GPR158-PLCXD2 interaction. Together, our findings reveal how a postsynaptic receptor signaling complex regulates the local lipid microenvironment to control SA abundance required for the proper maturation of dendritic spines.

neuroscience↗