Olig1 is required for noggin‐induced neonatal myelin repair

Abstract

Objective Neonatal white matter injury (NWMI) is a lesion found in preterm infants that can lead to cerebral palsy. Although antagonists of bone morphogenetic protein (BMP) signaling, such as Noggin, promote oligodendrocyte precursor cell (OPC) production after hypoxic-ischemic injury, the downstream functional targets are poorly understood. The bHLH protein Olig1 promotes oligodendrocyte (OL) development and is essential during remyelination in adult mice. Here, we investigated whether Olig1 function is required downstream of BMP antagonism for the response to injury in the neonatal brain. Methods We used wild type and Olig1 mutant mice subjected to neonatal stroke and postnatal neural progenitor cultures, and we analyzed Olig1 expression in human postmortem samples from neonates that suffered hypoxic-ischemic encephalopathy (HIE). Results Olig1-null neonatal mice showed significant hypomyelination after moderate neonatal stroke. Surprisingly, damaged white matter tracts in Olig1−/− mice lacked Olig2+ OPCs and instead proliferating neuronal precursors and GABAergic interneurons were present. We demonstrate that Noggin-induced OPC production requires Olig1 function. In postnatal neural progenitors, Noggin governs production of OLs versus interneurons through Olig1-mediated repression of Dlx1/2 transcription factors. Additionally, we observed that Olig1 and the BMP signaling effector pSMAD1/5/8 are elevated in the subventricular zone (SVZ) of human infants with HIE compared to controls. Interpretation These findings indicate that Olig1 has a critical function in the regulation of the postnatal neural progenitor cell production in response to Noggin.

Development of an Early Prediction Model for Subarachnoid Hemorrhage With Genetic and Signaling Pathway Analysis

“…To answer the second question, we used mathematical algorithms to explore five potential gene biomarkers (Tk1, Cyr61, Olig1, Slc6a9, and Pcolce2), considering the impact of both SAH and LCN2 treatment at different time points, and also used the manually reviewed experimental evidence to demonstrate that Cyr61 (Yu et al, 2018), Olig1 (Sabo et al, 2017), and Slc6a9 (Huang et al, 2016) were closely related to SAH. Although Tk1 and Pcolce2 have not been reported to be associated with SAH, we will investigate their connections in future work.…”

“…The results demonstrate that LCN2 (Warszawska et al, 2013) can effectively intervene in or treat SAH from a cell signaling pathway perspective. Also, three key genes were identified and validated by manual review of the experimental evidence (Huang et al, 2016;Sabo et al, 2017;Yu et al, 2018). Finally, the results showed that the ensemble learning model performed better for early SAH prediction than the classical LR, SVM, and Naive-Bayes models.…”

“…This resulted in five candidate genes (Tk1, Cyr61, Olig1, Slc6a9, and Pcolce2). However, manual review of the experimental evidence indicated that only Cyr61 (Yu et al, 2018), Olig1 (Sabo et al, 2017), and Slc6a9 (Huang et al, 2016) were closely related to SAH, cerebral hemorrhage, and brain injury. Therefore, we considered these three genes (Figure 2, Table S9) to be potential biomarkers for SAH.…”

“…First, manual review of the experimental evidence (Osuka et al, 2006;Majdalawieh et al, 2007;Hanafy et al, 2010;Hao et al, 2014;Kwon et al, 2015;Yu et al, 2018) demonstrates that we could intervene or treat SAH by targeting LCN2 from a cell signaling pathway perspective. Next, we explore three key genes that are sensitive to both SAH and LCN2 treatment, again using manual review of the experimental evidence (Huang et al, 2016;Sabo et al, 2017;Yu et al, 2018) to cross-validate the relationships between SAH and these key genes. Finally, we show that our SAH early prediction ensemble-learning model outperforms the classical LR, Naive-Bayes, and SVM models.…”

Pediatric brain repair from endogenous neural stem cells of the subventricular zone

“…Moreover, they found that elevated levels of transforming growth factor-β (TGF-β) were produced in the H-I brain and that the aberrant levels of GFAP in the SVZ could be reduced by administering an antagonist to the TGF-β receptor, activin-like kinase receptor-5 (65). In a recent study by Sabo et al (66), they found evidence for increased bone morphogenetic protein signaling in Olig1+ SVZ cells, which correlated with decreased production of oligodendrocytes and increased production of interneurons (66).…”