Biology subjects

Taketo, M. M. M.

Publications and source records attributed to Taketo, M. M. M..

3 recordsLinked to original sources

bioRxiv2024

Age-induced BMP signaling inhibits the ICAT-mediated Wnt pathway to promote osteoarthritis.

Osteoarthritis (OA) is a highly prevalent and debilitating musculoskeletal disorder that affects billions of aging individuals worldwide, causing chronic pain, impaired mobility, and a substantial decline in quality of life, yet effective disease-modifying therapies remain unavailable. Moreover, existing experimental models, however, inadequately capture the complex, age-related factors that contribute to OA pathogenesis, limiting our understanding of underlying molecular mechanisms and hindering therapeutic development. To address this gap, we examined mouse articular cartilage (AC) during natural aging, without surgical or chemical intervention. In young AC, BMP ligand expression is restricted to the bone-cartilage junction, limiting BMP signaling despite widespread BMPR1A receptor expression, while Wnt/{beta}-catenin signaling predominates in the outer layers. With aging, BMP ligand expression expands throughout the cartilage, leading to widespread activation of BMP signaling, which induces ICAT expression, a known inhibitor of Wnt/{beta}-catenin signaling. This elevated BMP signaling triggers chondrocyte hypertrophy while concurrently suppressing Wnt/{beta}-catenin activity. Moreover, genetic or pharmacological activation of BMP signaling in young AC recapitulates the cellular and molecular features of aged cartilage, independent of chronological age. Collectively, our findings demonstrate that an age-dependent shift in BMP-Wnt signaling disrupts AC homeostasis and drives OA progression in mice. Author SummaryDespite the prevalence of osteoarthritis in aging individuals, there are no effective treatments that can stop or reverse disease progression. In this study, we investigated how joint cartilage changes during natural aging in mice. We observed that healthy, young articular cartilage exhibits robust Wnt/{beta}-catenin with minimal BMP siganling. With age, this balance shifts, with BMP signaling becoming dominant, coupled with reduced Wnt/{beta}-catenin activity. This disruption of Wnt-BMP homeostasis induces the pathogenesis of OA. Importantly, local inhibition of BMP signaling significantly alleviates the severity of the disease. Overall, these results show that age-associated changes in key signaling pathways drive OA progression and suggest potential targets for therapeutic intervention. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/616036v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@b2be12org.highwire.dtl.DTLVardef@dcb1f3org.highwire.dtl.DTLVardef@126fc40org.highwire.dtl.DTLVardef@7af96c_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2021

Deleting in vivo β-catenin degradation domain in mouse hepatocytes drives hepatocellular carcinoma or hepatoblastoma-like tumors

Background and aimsOne-third of hepatocellular carcinomas (HCCs) have mutations that activate the {beta}-catenin pathway with mostly CTNNB1 mutations. Mouse models using Adenomatous polyposis coli (Apc) loss-of-functions (LOF) are widely used to mimic {beta}-catenin-dependent tumorigenesis. Considering the low prevalence of APC mutations in human HCCs we aimed to generate hepatic tumors through CTNNB1 exon 3 deletion ({beta}cat{Delta}ex3) and to compare them to hepatic tumors with Apc LOF engineered through a frameshift in exon 15 (Apcfs-ex15). MethodsWe used hepatic-specific and inducible Cre-lox mouse models as well as a hepatic-specific in vivo CRISPR/Cas9 approach using AAV vectors, to generate Apcfs-ex15 and {beta}cat{Delta}ex3 hepatic tumors harboring activation of the {beta}-catenin pathway. Tumors generated by the Cre-lox models were analyzed phenotypically using immunohistochemistry and were selected for transcriptomic analysis using RNA-sequencing. Mouse RNAseq data were compared to human RNAseq data (normal tissues (8), HCCs (48) and hepatoblastomas (9)) in an integrative analysis. Tumors generated via CRISPR were analyzed using DNA sequencing and immunohistochemistry. ResultsMice with {beta}cat{Delta}ex3 alteration in hepatocytes developed liver tumors. Generated tumors were indistinguishable from those arising in Apcfs-ex15 mice. Both Apcfs-ex15 and {beta}cat{Delta}ex3 mouse models induced two phenotypically distinct tumors (differentiated or undifferentiated). Integrative analysis of human and mouse tumors showed that mouse differentiated tumors are close to human well differentiated CTNNB1-mutated tumors, while undifferentiated ones are closer to human mesenchymal hepatoblastomas, and are activated for YAP signaling. ConclusionApcfs-ex15 and {beta}cat{Delta}ex3 mouse models similarly induce tumors transcriptionally close to either well differentiated {beta}-Catenin activated human HCCs or mesenchymal hepatoblastomas.

cancer biology↗

bioRxiv2020

Canonical Wnt-signaling modulates the tempo of dendritic growth of adult-born hippocampal neurons

In adult hippocampal neurogenesis neural stem/progenitor cells generate new dentate granule neurons that contribute to hippocampal plasticity. The establishment of a morphologically defined dendritic arbor is central to the functional integration of adult-born neurons. Here, we investigated the role of canonical Wnt/{beta}-catenin-signaling in dendritogenesis of adult-born neurons. We show that canonical Wnt-signaling follows a biphasic pattern, with high activity in stem/progenitor cells, attenuation in early immature neurons, and re-activation during maturation, and demonstrate that the biphasic activity pattern is required for proper dendrite development. Increasing {beta}-catenin-signaling in maturing neurons of young adult mice transiently accelerated dendritic growth, but eventually resulted in dendritic defects and excessive spine numbers. In middle-aged mice, in which protracted dendrite and spine development was paralleled by lower canonical Wnt-signaling activity, enhancement of {beta}-catenin-signaling restored dendritic growth and spine formation to levels observed in young adult animals. Our data indicate that precise timing and strength of {beta}-catenin-signaling is essential for the correct functional integration of adult-born neurons and suggest Wnt/{beta}-catenin-signaling as a pathway to ameliorate deficits in adult neurogenesis during aging.

neuroscience↗