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1.
J Cell Biol ; 220(10)2021 10 04.
Article in English | MEDLINE | ID: mdl-34328499

ABSTRACT

Lumen morphogenesis results from the interplay between molecular pathways and mechanical forces. In several organs, epithelial cells share their apical surfaces to form a tubular lumen. In the liver, however, hepatocytes share the apical surface only between adjacent cells and form narrow lumina that grow anisotropically, generating a 3D network of bile canaliculi (BC). Here, by studying lumenogenesis in differentiating mouse hepatoblasts in vitro, we discovered that adjacent hepatocytes assemble a pattern of specific extensions of the apical membrane traversing the lumen and ensuring its anisotropic expansion. These previously unrecognized structures form a pattern, reminiscent of the bulkheads of boats, also present in the developing and adult liver. Silencing of Rab35 resulted in loss of apical bulkheads and lumen anisotropy, leading to cyst formation. Strikingly, we could reengineer hepatocyte polarity in embryonic liver tissue, converting BC into epithelial tubes. Our results suggest that apical bulkheads are cell-intrinsic anisotropic mechanical elements that determine the elongation of BC during liver tissue morphogenesis.


Subject(s)
Anisotropy , Bile Canaliculi/metabolism , Cell Membrane/metabolism , Hepatocytes/metabolism , Animals , Cells, Cultured , Female , Mice , Mice, Inbred C57BL , Mice, Transgenic , Organogenesis , Pregnancy
2.
Mol Cell Neurosci ; 72: 101-13, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26829712

ABSTRACT

Mutations that result in the defective trafficking of γ2 subunit containing GABAA receptors (γ2-GABAARs) are known to reduce synaptic inhibition. Whether perturbed clustering of non-mutated GABAARs similarly reduces synaptic inhibition in vivo is less clear. In this study we provide evidence that the loss of postsynaptic γ2-GABAARs upon postnatal ablation of gephyrin, the major scaffolding protein of inhibitory postsynapses, from mature principal neurons within the forebrain results in reduced induction of long-term potentiation (LTP) and impaired network excitability within the hippocampal dentate gyrus. The preferential reduction in not only synaptic γ2-GABAAR cluster number at dendritic sites but also the decrease in γ2-GABAAR density within individual clusters at dendritic inhibitory synapses suggests that distal synapses are more sensitive to the loss of gephyrin expression than proximal synapses. The fact that these mice display behavioural features of anxiety and epilepsy emphasises the importance of postsynaptic γ2-GABAAR clustering for synaptic inhibition.


Subject(s)
Carrier Proteins/genetics , Long-Term Potentiation , Membrane Proteins/genetics , Prosencephalon/metabolism , Receptors, GABA-A/metabolism , Synaptic Potentials , Animals , Carrier Proteins/metabolism , Cell Line , Dentate Gyrus/cytology , Dentate Gyrus/metabolism , Dentate Gyrus/physiology , Male , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Neurons/metabolism , Neurons/physiology , Prosencephalon/cytology , Prosencephalon/physiology , Receptors, GABA-A/genetics , Synapses/metabolism , Synapses/physiology
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