Snf2h Drives Chromatin Remodeling to Prime Upper Layer Cortical Neuron Development.

Alterations in the homeostasis of either cortical progenitor pool, namely the apically located radial glial (RG) cells or the basal intermediate progenitors (IPCs) can severely impair cortical neuron production. Such changes are reflected by microcephaly and are often associated with cognitive defects. Genes encoding epigenetic regulators are a frequent cause of intellectual disability and many have been shown to regulate progenitor cell growth, including our inactivation of the Smarca1 gene encoding Snf2l, which is one of two ISWI mammalian orthologs. Loss of the Snf2l protein resulted in dysregulation of Foxg1 and IPC proliferation leading to macrocephaly. Here we show that inactivation of the closely related Smarca5 gene encoding the Snf2h chromatin remodeler is necessary for embryonic IPC expansion and subsequent specification of callosal projection neurons. Telencephalon-specific Smarca5 cKO embryos have impaired cell cycle kinetics and increased cell death, resulting in fewer Tbr2+ and FoxG1+ IPCs by mid-neurogenesis. These deficits give rise to adult mice with a dramatic reduction in Satb2+ upper layer neurons, and partial agenesis of the corpus callosum. Mice survive into adulthood but molecularly display reduced expression of the clustered protocadherin genes that may further contribute to altered dendritic arborization and a hyperactive behavioral phenotype. Our studies provide novel insight into the developmental function of Snf2h-dependent chromatin remodeling processes during brain development.

Exploration of the Inter-Relationships Between Obesity, Physical Inactivity, Inflammation, and Low Back Pain.

STUDY DESIGN: Retrospective analysis wherein 103 patients were considered, and 76 patients were included: 49 were classified as chronic non-specific low back pain (CNSLBP) (Study group) and 27 had identifiable cases of specific chronic low back pain (LBP) (Control group). OBJECTIVE: Elucidate markers of systemic inflammation in patients with CNSLBP. SUMMARY OF BACKGROUND DATA: Mechanisms of LBP are poorly understood. Pro-inflammatory cytokines are increased in obesity and involved with pain modulation; we previously proposed a theoretical model of their mediating role in LBP. METHODS: Demographic information was acquired via questionnaire, chart review, and blood test data. Univariate analysis identified factors associated with CNSLBP and markers of systemic inflammation. A receiver operating curve and Youden Index were used to select optimal cut-off points for elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Multivariable logistic regression analysis calculated the adjusted strength of relationship between factors that were proposed in our theoretical model for CNSLBP. RESULTS: Unadjusted CRP was significantly correlated with ESR (R = 0.63, P < 0.0001) and body mass index (BMI) (R = 0.38, P = 0.0015). Physically inactive patients had significantly higher CRP (6.1 vs. 1.2, P = 0.0050). ESR was significantly correlated with number of comorbidities (R = 0.34, P = 0.0047), BMI (R = 0.38, P = 0.0014), and age (R = 0.36, P = 0.0026). Physically inactive patients (10.4 vs. 3.6, P = 0.0001) and females (11.2 vs. 6.4, P = 0.0422) had significantly higher ESR. Adjusted analyses indicated significant relationships between physical inactivity and markers of systemic inflammation (adjusted odds ratios for ESR and CRP: 15.9, P = 0.0380; 15.2, P = 0.0272, respectively), and between elevated CRP and CNSLBP (adjusted odds ratio: 8.0, P = 0.0126). CONCLUSION: Systemic inflammation may act as a mediator for physical inactivity and obesity in the pathogenesis of CNSLBP. LEVEL OF EVIDENCE: 2.

Voluntary Running Triggers VGF-Mediated Oligodendrogenesis to Prolong the Lifespan of Snf2h-Null Ataxic Mice.

Exercise has been argued to enhance cognitive function and slow progressive neurodegenerative disease. Although exercise promotes neurogenesis, oligodendrogenesis and adaptive myelination are also significant contributors to brain repair and brain health. Nonetheless, the molecular details underlying these effects remain poorly understood. Conditional ablation of the Snf2h gene impairs cerebellar development producing mice with poor motor function, progressive ataxia, and death between postnatal days 25-45. Here, we show that voluntary running induced an endogenous brain repair mechanism that resulted in a striking increase in hindbrain myelination and the long-term survival of Snf2h cKO mice. Further experiments identified the VGF growth factor as a major driver underlying this effect. VGF neuropeptides promote oligodendrogenesis in vitro, whereas Snf2h cKO mice treated with full-length VGF-encoding adenoviruses removed the requirement of exercise for survival. Together, these results suggest that VGF delivery could represent a therapeutic strategy for cerebellar ataxia and other pathologies of the CNS.