Single-cell Transcriptomics Resolves Intermediate Glial Progenitors and Uncovers a Pivotal Determinant of Cell Fate and Gliomagenesis

The identity and heterogeneity of glial progenitors and their contributions to brain tumor malignancy remain elusive. By applying lineage-targeted single-cell transcriptomics, we uncover an unanticipated diversity of glial progenitor pools with unique molecular identities in developing brain. Our analysis identifies distinct transitional intermediate states and their divergent developmental trajectories in astroglial and oligodendroglial lineages. Moreover, intersectional analysis uncovers analogous intermediate progenitors during brain tumorigenesis, wherein oligodendrocyte-progenitor intermediates are abundant, hyper-proliferative and progressively reprogrammed towards a stem-like state susceptible to further malignant transformation. Similar actively cycling intermediate progenitors are prominent components in human gliomas with distinct driver mutations. We further unveil lineage-driving networks underlying glial fate specification and identify Zfp36l1 as necessary for oligodendrocyte-astrocyte lineage transition and glioma growth. Together, our results resolve the dynamic repertoire of common and divergent glial progenitors during development and tumorigenesis and highlight Zfp36l1 as a molecular nexus for balancing glial cell-fate decision and controlling gliomagenesis. By applying lineage-targeted single-cell transcriptomics analysis, Weng and colleagues uncover distinct intermediate glial progenitors in the neonatal brain, and their malignant counterparts in murine and human gliomas. Lineage-driving network analysis further identifies Zfp36l1 as a pivotal regulator for glial fate specification and glioma growth.