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LIN28A overexpression has been identified in malignant brain tumors called embryonal tumors with multilayered rosettes (ETMR) but its specific role during brain development remains largely unknown. Radial glia cells of the ventricular zone (VZ) are proposed as a cell of origin for ETMR. We asked whether an overexpression of LIN28A in such cells might affect brain development or result in the formation of brain tumors.Constitutive overexpression of LIN28A in hGFAP-cre::lsl-Lin28A (GL) mice led to a transient increase of proliferation in the cortical VZ at embryonic stages but no postnatal brain tumor formation. Postnatally, GL mice displayed a pyramidal cell layer dispersion of the hippocampus and altered spine and dendrite morphology, including reduced dendritic spine densities in the hippocampus and cortex. GL mice displayed hyperkinetic activity and differential quantitative MS-based proteomics revealed altered time dependent molecular functions regarding mRNA processing and spine morphogenesis. Phosphoproteomic analyses indicated a downregulation of mTOR pathway modulated proteins such as Map1b being involved in microtubule dynamics.In conclusion, we show that Lin28A overexpression transiently increases proliferation of neural precursor cells but it is not sufficient to drive brain tumors in vivo. In contrast, Lin28A impacts on protein abundancy patterns related to spine morphogenesis and phosphorylation levels of proteins involved in microtubule dynamics, resulting in decreased spine densities of neurons in the hippocampus and cortex as well as in altered behavior. Our work provides new insights into the role of LIN28A for neuronal morphogenesis and development and may reveal future targets for treatment of ETMR patients.

OBJECTIVE The Chicago Chiari Outcome Scale (CCOS) serves as a standardized clinical outcome evaluation tool among patients with Chiari malformation type I (CM-I). While the reliability of this scale has been proven for pediatric patients, the literature lacks CCOS validation when used solely in adults. Therefore, this study aimed to determine the validity of the CCOS in an external cohort of adult patients. METHODS The authors retrospectively analyzed the medical records of symptomatic patients with CM-I who underwent posterior fossa decompression between 2010 and 2018 in six neurosurgical departments. Each patient was clinically assessed at the latest available follow-up. Gestalt outcome was determined as improved, unchanged, or worsened compared with the preoperative clinical state. Additionally, the CCOS score was calculated for each patient based on the detailed clinical data. To verify the ability of the CCOS to determine clinical improvement, the area under the receiver operating characteristic (AUROC) curve was evaluated. A logistic regression analysis using all four components of the CCOS (pain symptoms, nonpain symptoms, functionality, and complications) was performed to establish predictors of the improved outcome. RESULTS Seventy-five individuals with a mean age of 42 ± 15.32 years were included in the study. The mean follow-up duration was 52 ± 33.83 months. Considering gestalt outcome evaluation, 41 patients (54.7%) were classified as improved, 24 (32%) as unchanged, and 10 (13.3%) as worsened. All patients with a CCOS score of 14 or higher improved, while all those with a CCOS score of 8 or lower worsened. The AUROC was 0.986, suggesting almost perfect accuracy of the CCOS in delineating clinical improvement. A CCOS score of 13 showed high sensitivity (0.93) and specificity (0.97) for identifying patients with clinical improvement. Additionally, a meaningful correlation was found between higher CCOS scores in each component and better outcomes. Patient stratification by total CCOS score showed that those categorized as improved, unchanged, and worsened scored prevalently between 13 and 16 points, 10 and 12 points, and 4 and 9 points, respectively. CONCLUSIONS In this adult cohort, the CCOS was found to be almost perfectly accurate in reflecting postoperative clinical improvement. Moreover, all four CCOS components (pain symptoms, nonpain symptoms, functionality, and complications) significantly correlated with patient clinical outcomes.