C. elegans CEH-43/DLX drives convergent astrocyte differentiation by sequential control of axon guidance and synaptic gene expression programs

Abstract

Mammalian radial glia can remodel into astrocytes, which acquire common transcriptional identities despite arising from spatially and lineally distinct progenitors. The molecular mechanisms underlying convergent radial glia-to-astrocyte transformation are not fully understood. To identify regulators of this process, we investigated the development of Caenorhabditis elegans CEPsh glia, astrocyte-like glial cells that arise through remodeling of radial glia-like precursors from distinct progenitor lineages. Using lineage-restricted single-cell RNA sequencing, we characterized a temporally resolved transcriptional program underlying CEPsh glia development. We found that transcriptionally disparate nascent CEPsh glia rapidly converge onto a shared radial glia-like state that promotes nerve ring (brain) assembly, before undergoing progressive, cell division-independent maturation into astrocyte-like glia. We identify the distal-less transcription factor CEH-43 as a key regulator of both developmental phases. CEH-43 directly controls the expression of embryonic genes involved in axon guidance as well as postembryonic genes required for mature glial functions. Comparative transcriptomic and histological analyses reveal conserved molecular features between C. elegans CEPsh glia and mammalian astrocytes, including astrocytic expression of the CEH-43 homolog DLX1. Together, our findings uncover a transcriptional program governing convergent CEPsh glia differentiation and maturation and suggest that core mechanisms of astrocyte development may be evolutionarily conserved.