Biology subjects

Stoufflet, J.

Publications and source records attributed to Stoufflet, J..

4 recordsLinked to original sources

bioRxiv2025

GPR161 mechanosensitivity at the primary cilium drives neuronal saltatory migration

The saltatory migration of neurons is essential for brain formation. Whether mechanical stimuli regulate this process is unknown. Here we show that the primary cilium acts as a mechanical sensor through GPR161. Using an ex vivo neuronal migration model and microfluidic assays, we demonstrate that fluid shear stress induces migration via the mechanoreceptor GPR161 at the primary cilium, with its mechanosensitive Helix 8 being essential. We demonstrate that GPR161 activates a recently discovered cAMP/PKA signaling pathway leading to the phosphorylation of NDE1, a dynein complex regulator, and microtubule organization to regulate migration. These findings unveil a dynamic primary cilium-based pathway sensing mechanical stimulus to drive cyclic saltatory neuronal migration during brain development.

neuroscience↗

bioRxiv2023

FMRP regulates postnatal neuronal migration via MAP1B

The Fragile X Syndrome (FXS) represents the most prevalent form of inherited intellectual disability and is the first monogenic cause of Autism Spectrum Disorder. FXS results from the absence of the RNA-binding protein FMRP (Fragile X Messenger Ribonucleoprotein). Neuronal migration is an essential step of brain development allowing displacement of neurons from their germinal niches to their final integration site. The precise role of FMRP in neuronal migration remains largely unexplored. Using live imaging of postnatal Rostral Migratory Stream (RMS) neurons in Fmr1-null mice, we observed that the absence of FMRP leads to delayed neuronal migration and altered trajectory, associated with defects of centrosomal movement. RNA-interference-induced knockdown of Fmr1 shows that these migratory defects are cell-autonomous. Notably, the primary FMRP mRNA target implicated in these migratory defects is MAP1B (Microtubule-Associated Protein 1B). Knocking-down MAP1B expression effectively rescued most of the observed migratory defects. Finally, we elucidate the molecular mechanisms at play by demonstrating that the absence of FMRP induces defects in the cage of microtubules surrounding the nucleus of migrating neurons, which is rescued by MAP1B knockdown. Our findings reveal a novel neurodevelopmental role for FMRP in collaboration with MAP1B, jointly orchestrating neuronal migration by influencing the microtubular cytoskeleton.

neuroscience↗

bioRxiv2021

Myosin-1b interacts with UNC45A and controls intestinal epithelial morphogenesis

Vesicle trafficking and the establishment of apico-basal polarity are essential processes in epithelium morphogenesis. Myosin-1b, an actin-motor able to bind membranes, regulates membrane shaping and vesicle trafficking. Here, we investigate Myosin-1b function in gut morphogenesis and congenital disorders using cell line and zebrafish larvae as well as patient biopsies. In a 3D Caco-2 cyst model, lumen formation is impaired in absence of Myosin-1b. In zebrafish, both Morpholino knock-down and genetic mutation of myo1b result in intestinal bulb epithelium folding defects associated with vesicle accumulation, reminiscent of a villous atrophy phenotype. We show that Myosin-1b interacts with the chaperone UNC45A, genetic deletion of which also results in gut folding defects in zebrafish. Loss of function mutations in UNC45A have been reported in complex hereditary syndromes, notably exhibiting intestinal disorders associated with villous atrophy. In UNC45A-depleted cells and in patient biopsies, Myosin-1b protein level is strikingly decreased. The appearance of Myosin-1b aggregates upon proteasome inhibition in cells points at a degradation mechanism of misfolded Myosin-1b in the absence of its chaperone. In conclusion, Myosin-1b plays an unexpected role in the development of the intestinal epithelium folds or villi downstream UNC45A, establishing its role in the gut defects reported in UNC45A patients. Summary statementMyosin-1b is important for intestinal epithelium folding during zebrafish development and participates in the villous atrophy clinical manifestation downstream UNC45A loss of function.

developmental biology↗

bioRxiv2019

Primary cilium cAMP regulates cyclic saltatory neuronal migration at the centrosome

The primary cilium (PC) is a small centrosome-assembled organelle, protruding from the surface of most eukaryotic cells. It plays a key role in cell migration, but the underlying mechanisms are unknown. Here, we show that the PC regulates neuronal migration via cAMP production activating centrosomal Protein Kinase A (PKA). Biosensor live-imaging revealed a periodic cAMP hotspot at the centrosome of embryonic, postnatal and adult migrating neurons. Genetic ablation of the PC, or knock-down of ciliary Adenylate Cyclase 3, caused hotspot disappearance and migratory defects, with defective centrosome/nucleus coupling and altered nucleokinesis. Delocalization of PKA from the centrosome phenocopied the migratory defects. Our results show that the PC and centrosome form a single cAMP-signaling unit dynamically regulating migration, further highlighting the centrosome as a signaling hub. The primary cilium regulates neuronal migration via cyclic AMP production activating Protein Kinase A at the centrosome

neuroscience↗