Biology subjects

Hausser, A.

Publications and source records attributed to Hausser, A..

6 recordsLinked to original sources

bioRxiv2026

Interplay between β-catenin transcriptional and cell-cell junction activity regulates homeostasis and collective dynamics in the intestinal epithelium

Wnt signaling is crucial for stem cell maintenance during development and homeostasis, and its dysregulation is implicated in cancers across multiple tissues. {beta}-catenin, the primary mediator of canonical Wnt signaling, is also a crucial adaptor protein at cell-cell junctions and is required for maintaining tissue integrity. How the interplay and potential competition between these discrete functions of {beta}-catenin influences tissue homeostasis and organization is not well understood. Here, we address this open question in the intestinal epithelium, which is highly dependent on Wnt signaling during homeostasis and regeneration. Ectopic activation of Wnt signaling in intestinal organoids by pharmacological or genetic perturbation leads to tissue fluidification and loss of epithelial integrity, while disrupting Wnt activity perturbs intracellular {beta}-catenin localization and dynamics at cell-cell junctions. Stabilization of cell-cell junctions increases {beta}-catenin accumulation at junctions at the expense of nuclear localization, while junctional perturbation leads to {beta}-catenin release from junctions into the cytoplasm, leading to dysregulation of Wnt signaling. Together, our findings indicate that in tissues with active Wnt signaling, the interplay between junction- and signaling-associated {beta}-catenin is crucial for stem cell regulation and tissue homeostasis.

cell biology↗

bioRxiv2025

PKD3 localizes to late endosomes to maintain Rab7-dependent endolysosomalhomeostasis

Protein kinase D3 (PKD3) is an important regulator of triple-negative breast cancer (TNBC) progression by promoting invasion, proliferation, and stem cell maintenance. However, the mechanism underlying these cellular functions has remained unclear. Here, we report that endogenous PKD3 localizes to Rab7/Lamp1-positive vesicles in MDA-MB-231 cells cultured on stiff matrices. Notably, upon PKD3 depletion the size of Rab7-positive vesicles is smaller. This correlates with impaired endosomal acidification, which is associated with dysregulated Wnt signaling and a decline in stemness. Our data thus unveil a previously unrecognized role of PKD3 in regulating endolysosomal dynamics that contributes to the maintenance of the cancer stem cell population.

cell biology↗

bioRxiv2022

Comparative analysis of actin visualization by genetically encoded probes in cultured neurons

Actin cytoskeleton predominantly regulates the formation and maintenance of synapses by controlling dendritic spine morphology and motility. To visualize actin dynamics, actin molecules can be labelled by genetically fusing fluorescent proteins to actin monomers or using fluorescently tagged actin-binding proteins or single-chain anti-actin antibodies. However, the effects of these labels on the morphology of neurons have not been quantitatively compared yet. In the present study, we analysed Actin-Chromobody-GFP, LifeAct-GFP and EGFP-actin with respect to their effects on actin-related features in mouse cultured hippocampal neurons. The actin-binding probes LifeAct and Actin-Chromobody showed similar affinity to F-actin, and along with EGFP-actin, were enriched in dendritic protrusions. In contrast to EGFP-actin, neither of these constructs was able to detect subtle changes in actin remodelling between mature mushroom shaped spine and less developed filopodia. None of the compared probes altered filopodial motility compared to control EGFP expression, however, within 24 hours expression, minor changes in dendritic spine morphology and density were visible. Furthermore, while EGFP-actin and LifeAct-GFP expression did not alter dendritic arborization, AC-GFP expressing neurons displayed a reduced dendritic arborization. We therefore conclude that careful consideration of cellular consequences is required before performing experiments with a particular actin labelling probe in primary neurons.

cell biology↗

bioRxiv2022

PKD autoinhibition in trans regulates activation loop autophosphorylation in cis

Phosphorylation is a ubiquitous mechanism by which signals are transduced in cells. Protein kinases, enzymes that catalyze the phospho-transfer reaction are, themselves, often regulated by phosphorylation. Paradoxically, however, a substantial fraction of the more than 500 human protein kinases are capable of catalyzing their own activation loop phosphorylation. Commonly, these kinases perform this autophosphorylation reaction in trans, whereby transient dimerization leads to the mutual phosphorylation of the activation loop of the opposing protomer. In this study, we demonstrate that Protein Kinase D (PKD) is regulated by the inverse mechanism of dimerization-mediated trans-autoinhibition, followed by activation loop autophosphorylation in cis. We show that PKD forms a stable face-to-face homodimer that is incapable of either auto- or substrate phosphorylation. Dissociation of this trans-autoinhibited dimer results in activation loop autophosphorylation, which occurs exclusively in cis. Phosphorylation serves to increase PKD activity and prevent trans-autoinhibition, thereby switching PKD on. Our findings not only reveal the mechanism of PKD regulation, but have profound implications for the regulation of many other eukaryotic kinases.

biochemistry↗

bioRxiv2020

PKD promotes activity-dependent AMPA receptorendocytosis in hippocampal neurons

AMPA type glutamate receptors (AMPARs) mediate the majority of fast excitatory neurotransmission in the brain. The continuous trafficking of AMPARs into and out of synapses is a core feature of synaptic plasticity, which is considered as the cellular basis of learning and memory. The molecular mechanisms underlying the postsynaptic AMPAR trafficking, however, are still not fully understood. In this work, we demonstrate that the Protein Kinase D (PKD) family promotes basal and activity-induced AMPAR endocytosis in primary hippocampal neurons. Pharmacological inhibition of PKD increased synaptic levels of GluA1-containing AMPARs, slowed down their endocytic trafficking and increased neuronal network activity. By contrast, ectopic expression of constitutive active PKD decreased the synaptic level of AMPARs, while increasing their co-localization with early endosomes. Our results thus establish an important role for PKD in the regulation of postsynaptic AMPAR trafficking during synaptic plasticity.

neuroscience↗

bioRxiv2016

Sphingolipid metabolic flow controls phosphoinositide turnover at thetrans Golgi network

Sphingolipids are membrane lipids, which are globally required for eukaryotic life. Sphingolipid composition varies among endomembranes with pre- and post-Golgi compartments being poor and rich in sphingolipids, respectively. Thanks to this different sphingolipid content, pre- and post-Golgi membranes serve different cellular functions. Nevertheless, how subcellular sphingolipid levels are maintained in spite of trafficking and metabolic fluxes is only partially understood. Here we describe a homeostatic control circuit that controls sphingolipid levels at the trans Golgi network. Specifically, we show that sphingomyelin production at the trans Golgi network triggers a signalling reaction leading to PtdIns(4)P dephosphorylation. Since PtdIns(4)P is required for cholesterol, and sphingolipid transport to the trans Golgi network, PtdIns(4)P consumption leads to the interruption of this transport in response to excessive sphingomyelin production. Based on this evidence we envisage a model where this homeostatic circuit maintains the sphingolipid composition of trans Golgi network and thus of post-Golgi compartments constant, against instant fluctuations in the sphingolipid biosynthetic flow.

cell biology↗