Biology subjects

Vacher, J.

Publications and source records attributed to Vacher, J..

5 recordsLinked to original sources

bioRxiv2026

Natural scene segmentation dynamics reveal iterative Bayesian inference

The visual system operates by segmenting visual inputs into distinct perceptual objects. Segmentation is dynamic, as revealed by the tempo of perceptual choices and neural activity in visual cortex. Dynamics for natural stimuli however, are poorly understood because natural scene segmentation is ambiguous and subjective. We measured subjective human segmentation maps for natural images using an innovative paradigm, and uncovered richer spatiotemporal dynamics than predicted by current theories of segmentation. To explain these dynamics, we introduced Iterative Bayesian Inference algorithms for segmentation that iteratively integrate visual inputs with the prior expectation that objects are spatially compact. When visual inputs were consistent with such a spatial prior, iterative inference was faster. This predicted relationship between spatial prior and inferential dynamics was evident in our data, and correctly reflected each individual participants spatial biases. We conclude that iterative Bayesian inference sets the tempo for a fundamental function of natural vision.

neuroscience↗

bioRxiv2026

OSTM1 is a ubiquitin E3 ligase that suppresses B-cell malignancy by activating the cAMP/PKA/CREB pathway

Osteoclastogenesis-associated transmembrane protein 1 (OSTM1) is a glycosylated, membrane-integral protein that regulates lysosomal homeostasis, with loss-of-function mutations causing autosomal recessive osteopetrosis. Through a whole-genome CRISPR/Cas9 screen, we identified OSTM1 as a previously unrecognized tumor suppressor in B-cell malignancies. Consistent with this role, OSTM1 is frequently deleted or downregulated across a broad spectrum of human B-cell cancers. In mice, B-cell-specific monoallelic or biallelic ablation of Ostm1 cooperates with Cdkn2a loss to drive lymphomagenesis with near-complete penetrance. Mechanistically, we uncover a cytosolic, non-glycosylated fraction of OSTM1 that functions as a ubiquitin E3 ligase to promote proteasomal degradation of phosphodiesterase 3B (PDE3B). As PDE3B hydrolyzes cAMP and suppresses the tumor-protective PKA/CREB/CREBBP signaling axis, loss of OSTM1 leads to PDE3B stabilization, attenuation of cAMP signaling, and enhanced oncogenic transformation. Together, our findings establish OSTM1 as a critical suppressor of B-cell lymphomagenesis through regulation of the cAMP/PKA/CREB pathway.

cancer biology↗

bioRxiv2025

The molecular and cellular interplay between the osteopetrosis-associated proteins SNX10, OSTM1, and CLC-7 during osteoclastogenesis

Bone-resorbing osteoclasts (OCLs) are large, multi-nucleated cells that are formed through well-regulated differentiation and cell fusion of monocyte-macrophage precursors. Disruption of OCL-mediated bone resorption perturbs bone formation, remodeling, and homeostasis that, in turn, can lead to severe illnesses, such as autosomal recessive osteopetrosis (ARO). Mutations in the intracellular trafficking-associated protein sorting nexin 10 (SNX10) lead to "OCL-rich" ARO, in which OCLs are produced but are inactive. Furthermore, OCL fusion is deregulated in SNX10-knockout (SKO) mice: mature mutant OCLs fuse continuously to generate gigantic cells, in vitro and in vivo, unlike wild-type OCLs that stop fusing with each other upon maturation. Mutations in CLC-7, the lysosomal voltage-gated Cl-/H+ exchanger, and OSTM1, the beta-chain of the exchanger, also induce ARO in humans and in mouse models, and are associated with the presence of large OCLs. This study explored the molecular interplay between SNX10, CLC-7 and OSTM1 by directly comparing the phenotypes of cultured OCLs lacking one of these proteins. We show that loss of SNX10, OSTM1, or CLC-7 leads to the formation of similarly-gigantic OCLs in culture, due to deregulated fusion between mature OCLs that proceeds with similar kinetics. All three proteins are associated with LAMP1-positive lysosomes, localized in both perinuclear and peripheral regions of mature wild-type OCLs. Co-immunoprecipitation studies indicated that SNX10 physically interacts with CLC-7. Notably, SNX10-KO OCLs exhibited a significant reduction in peripheral lysosomes containing CLC-7 and OSTM1, suggesting that SNX10 is required for their transport to the cell periphery. Taken together, these findings indicate that SNX10 regulates the subcellular distribution of lysosomes containing CLC-7 and OSTM1, thereby controlling both the fusion and functionality of mature OCLs.

cell biology↗

bioRxiv2021

PIKfyve inhibition reveals a novel role for Inpp4b in the regulation of PtdIns(3)P and lysosome dynamics

Lysosome membranes contain diverse phosphoinositide (PtdIns) lipids that co-ordinate lysosome function and dynamics. The PtdIns repertoire on lysosomes is tightly regulated by the action of diverse PtdIns kinases and phosphatases. Specific roles for PtdIns in lysosomal function and dynamics are currently unclear and require further investigation. PIKfyve, a lipid kinase which synthesizes PtdIns(3,5)P2 from PtdIns(3)P, controls lysosome "fusion-fission" cycles dynamics, autophagosome turnover and endocytic cargo delivery. We have recently characterized a role for INPP4B, a PtdIns phosphatase which hydrolyses PtdIns(3,4)P2 to form PtdIns(3)P, in the regulation of lysosomal biogenesis and function. To gain a better understanding of PtdIns homeostasis on lysosomes, we investigated the consequence of disrupting PIKfyve in Inpp4b-deficient mouse embryonic fibroblasts. Surprisingly, simultaneous inhibition of Inpp4b and PIKfyve functions impair lysosome "fission" dynamics and thereby exacerbate lysosome enlargement, inhibit autophagic flux. Further examination into the underlying processes that may explain exaggerated lysosome enlargement revealed elevated levels of lysosome associated PtdIns(3)P as contributing factors that control lysosome morphology in cells where Inpp4b and PIKfyve are disrupted. Overall, our study suggests that lysosomal functions are regulated by Inpp4b, through a paradoxical role in suppressing the induction of PtdIns(3)P production. SUMMARY STATEMENTIn this study we identify a novel crosstalk between Inpp4b and PIKfyve. This crosstalk regulates lysosome membrane phosphoinositide composition and lysosomal homeostasis. Our data demonstrate that Inpp4b restricts VPS34-dependent induction of PtdIns(3)P levels, which is activated upon apilimod-mediated PIKfyve inhibition. Through this mechanism, Inpp4b contributes to the regulation of lysosomal membrane dynamics and homeostasis.

cell biology↗

bioRxiv2021

INPP4B promotes leukemia by restricting leukemic stem cell differentiation through regulation of lysosomal functions

Signaling pathways that control vital features of leukemic stem cells including multipotency, self-renewal, clonal expansion and quiescence remain unclear. Emerging studies illustrate critical roles for lysosomes in hematopoietic and leukemic stem cell fate. By investigating consequences of INPP4B alterations in AML, we have discovered its role in driving leukemic stemness. We observed that INPP4B is highly expressed leukemic stem cell populations and Inpp4b-deficeint leukemias demonstrate increased disease latency, reduced leukemia initiating potential which is associated with a differentiated leukemic phenotype. Molecular analyses show that Inpp4b-deficient leukemias have compromised lysosomal gene expression, lysosomal content, and lysosomal activity. Our discovery of a novel pathway linking INPP4B, lysosomal biogenesis and leukemic stemness, provides a mechanism to explain the association of high INPP4B expression with poor AML prognosis, and highlights novel patient stratification strategies and LSC-specific leukemic therapies. Key PointsOur findings highlight a novel pathway linking INPP4B, lysosomal function and leukemic stemness that explains the prognostic role of INPP4B in AML. Our data reveal the utility of INPP4B as a biomarker of aggressive AML and provide a rationale to explore INPP4B and its associated function in lysosome biology as novel strategies to target LSC and AML

cancer biology↗