Single-nucleus RNA-seq analysis of Tox3 dependent gene expression in the mouse cerebellum

Here, we present a comprehensive atlas profiling 1,904 transcription regulators across organs, uncovering TOX3 as a potential co-activator of Atoh1 in cerebellar granule neuron progenitors. Tox3-deficient mice display severe ataxia and cerebellar hypoplasia, driven by depletion of granule neuron progenitors, diminished Atoh1 expression, and impaired primary cilia.

Single-nucleus RNA-seq analyses reveals compromised maintenance of the progenitor pool. TOX3 is also highly expressed in subsets of medulloblastoma, and its deletion reduces cerebellar neoplasia and prolongs survival in a mouse model. Mechanistically, Tox3 and Atoh1 co-occupy and synergistically activate E-boxes in shared target genes by up to 120-fold, including an ultra-conserved E-box downstream of Atoh1.