Galton, R. | bioRxiv Science

bioRxiv2026

Ependymomas are cancers of the pre-neural crest/roof plate lineage

Distinct molecular variants of the brain cancer ependymoma are distributed along the rostral-caudal extent of the central nervous system (CNS). Historically proposed to arise from ventricular ependyma, recent studies have suggested conflicting cellular origins, including the neural radial glia and the roof plate lineages. Using single-cell transcriptomics, immunohistochemistry, and lineage tracing, we demonstrate that ependymomas across all CNS compartments transcriptionally mirror MSX1+ve pre-neural crest/roof plate (Pre-NC/RP) lineage derivatives. Ependymoma subgroups recapitulate the spatial and molecular diversity of regional Pre-NC/RP populations, while retaining conserved MSX1 expression. Expression of the oncogenic fusion ZFTA-RELA within the murine Pre-NC/RP lineage generated tumors that faithfully resembled human ependymoma. These findings identify a common embryonic cellular origin for ependymomas and reconcile previously conflicting models of tumorigenesis.

developmental biology↗

bioRxiv2021

A somatic piRNA pathway regulates epithelial-to-mesenchymal transition of chick neural crest cells

In the metazoan germline, Piwi proteins play an essential regulatory role in maintenance of stemness and self-renewal by piRNA-mediated repression of transposable elements. To date, the activity of Piwi proteins and the piRNA pathway in vertebrates was believed to be confined to the gonads. Our results reveal expression of Piwil1 in a vertebrate somatic cell type, the neural crest-a migratory embryonic stem cell population. We show that Piwil1 is expressed at low levels throughout chick neural crest development, peaking just before neural crest cells undergo an epithelial-to-mesenchymal transition to leave the neural tube and migrate into the periphery. Importantly, loss of Piwil1 impedes neural crest emigration. Small RNA sequencing reveals somatic piRNAs with sequence signatures of an active ping pong loop. Coupled with Piwil1 knockout RNA-seq, our data suggest that Piwil1 regulates expression of the transposon derived gene ERNI in the chick dorsal neural tube, which in turn suppresses Sox2 expression to precisely control the timing of neural crest specification and emigration. Our work provides mechanistic insight into a novel function of the piRNA pathway as a regulator of somatic development in vertebrates.

developmental biology↗