Radial-glia-to-astrocyte trans-differentiation and astrocyte transcriptional convergence are coordinated by CEH-43/DLX in C. elegans

Abstract

Mammalian radial glia can remodel to become astrocytes, which acquire common transcriptional states despite spatially and lineally distinct origins. To uncover molecular programs driving convergent radial-glia-to-astrocyte transformation, we investigated development of C. elegans CEPsh astrocytes, which also arise from distinct progenitors without cell division. Using lineage-restricted single-cell RNA sequencing, we delineate a two-phase program for CEPsh astrocyte formation. Transcriptionally disparate nascent CEPsh glia rapidly acquire a common radial-glia-like state, facilitating nerve ring (brain) assembly. Subsequently, convergent CEPsh glia upregulate astrocyte-specific gene expression. Both phases require the distal-less transcription factor CEH-43, expressed in CEPsh glia and their progenitors. CEH-43 binds conserved astrocyte-expressed genes, cell-autonomously activating both early and late CEPsh glia-specific gene expression. CEH-43 misexpression is sufficient to induce CEPsh astrocyte reporter expression. We demonstrate that CEH-43 homologs, DLX1/2, are expressed in mouse astrocytes, and comparative transcriptomics reveal additional parallels. Our findings provide a molecular foundation for understanding cell-division-independent radial-glia-to-astrocyte transformation.