Transient regulation of focal adhesion via Tensin3 is required for nascent oligodendrocyte differentiation.

The differentiation of oligodendroglia from oligodendrocyte precursor cells (OPCs) to complex and extensive myelinating oligodendrocytes (OLs) is a multistep process that involves large-scale morphological changes with significant strain on the cytoskeleton. While key chromatin and transcriptional regulators of differentiation have been identified, their target genes responsible for the morphological changes occurring during OL myelination are still largely unknown. Here, we show that the regulator of focal adhesion, Tensin3 (Tns3), is a direct target gene of Olig2, Chd7, and Chd8, transcriptional regulators of OL differentiation. Tns3 is transiently upregulated and localized to cell processes of immature OLs, together with integrin-ß1, a key mediator of survival at this transient stage. Constitutive <i>Tns3</i> loss of function leads to reduced viability in mouse and humans, with surviving knockout mice still expressing Tns3 in oligodendroglia. Acute deletion of <i>Tns3</i> in vivo, either in postnatal neural stem cells (NSCs) or in OPCs, leads to a twofold reduction in OL numbers. We find that the transient upregulation of Tns3 is required to protect differentiating OPCs and immature OLs from cell death by preventing the upregulation of p53, a key regulator of apoptosis. Altogether, our findings reveal a specific time window during which transcriptional upregulation of Tns3 in immature OLs is required for OL differentiation likely by mediating integrin-ß1 survival signaling to the actin cytoskeleton as OL undergo the large morphological changes required for their terminal differentiation.

Criteria for inclusion in programs of functional restoration for chronic low back pain: Pragmatic Study.

BACKGROUND: Individuals with chronic low back pain (cLBP) may benefit from multimodal functional restoration programs (FRPs). OBJECTIVE: The aim of this study was to analyze characteristics of individuals with cLBP who were referred or not to an FRP. Because cLBP is a bio-psycho-social disorder, medical and social parameters were analysed. METHODS: This was an observational cross-sectional study performed in 2017 in 6 tertiary centres in France. Consecutive individuals with cLBP visiting a rheumatologist or physical medicine and rehabilitation physician were included. Individuals referred or not to an FRP were compared by demographic characteristics, duration of sick leave over the past year, self-reported physical activity>1h/week, pain (numeric rating scale 0-10), anxiety/depression (Hospital Anxiety and Depression Scale), disability (Oswestry Disability Index) and kinesiophobia (Tampa Kinesiophobia Scale). Univariate and multivariate logistic regression analyses were performed, estimating odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We included 147 individuals with cLBP. The mean (SD) age was 49 (12) years and 88 (60%) were women; 58 (38%) were referred to an FRP. On multivariate analysis, referral to an FRP was associated with reduced pain level (OR: 0.95, 95% CI: 0.91-0.99, for each 1-point increase in pain score), self-reported lack of physical activity (OR: 0.84, 95% CI: 0.72-0.98) and longer sick leave (OR: 1.03, 95% CI: 1.01-1.05, for 30 more days of sick leave). CONCLUSION: In this multicentric observational study, referral to an FRP was linked to pain, self-reported physical activity and sick leave but not medical characteristics assessed. These findings confirm the bio-psycho-social approach of FRPs for cLBP.