Nucleolus transformation and Pol1 activity pattern dual transcriptomes of neuronal subtype identity

Zagrebin, D.; Stefanov, S. R.; Brombacher, N.; Buschow, R.; Behrens, L.; Borisova, E.; Ilık, I. A.; Fauler, B.; Mielke, T.; Aktas, T.; Ambrozkiewicz, M. C.; Kretzmer, H.; Mayer, A.; Deuerling, E.; Kraushar, M. L.

doi:10.64898/2026.05.09.724016

bioRxiv · 10.64898/2026.05.09.724016

Nucleolus transformation and Pol1 activity pattern dual transcriptomes of neuronal subtype identity

Zagrebin, D.·Stefanov, S. R.·Brombacher, N.·Buschow, R.·Behrens, L.·Borisova, E.·Ilık, I. A.·Fauler, B.·Mielke, T.·Aktas, T.·Ambrozkiewicz, M. C.·Kretzmer, H.·Mayer, A.·Deuerling, E.·Kraushar, M. L.

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Abstract

Gene expression directs neuronal fate during development with multiple RNA polymerases in the nucleus. mRNA transcribed by Pol2 ultimately depends on the rRNA transcribed by Pol1 in the nucleolus, which generates a ribosome pool to control mRNA translation. How Pol1 activity is synchronized with the Pol2 transcriptome to direct gene expression and neuronal fate is unknown. By creating a high-resolution map of nucleoli in the developing neocortex, we discover that the nucleolus is restructured in neuronal lineages with distinct Pol1 activity. With a new method for rRNA and mRNA dual-transcriptome sequencing in single-cells, we reveal that rRNA transcription is neuronal subtype and stage specific. Rather than a general feature of neural progenitor differentiation, rRNA production peaks transiently in post-mitotic subcortical projection neurons, which have atypical nucleoli containing a single, large cavity. Pol1 inactivation redirects these neurons towards a distinct fate that expresses a hybrid of subcortical and intracortical projection neuron markers. Thus, nucleolar architecture and Pol1 activity pattern dual rRNA-mRNA transcriptome signatures of neuronal subtype identity.

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Zagrebin, D., Stefanov, S. R., Brombacher, N., Buschow, R., Behrens, L., Borisova, E., Ilık, I. A., Fauler, B., Mielke, T., Aktas, T., Ambrozkiewicz, M. C., Kretzmer, H., Mayer, A., Deuerling, E., Kraushar, M. L.. 2026-05-12. Nucleolus transformation and Pol1 activity pattern dual transcriptomes of neuronal subtype identity. https://doi.org/10.64898/2026.05.09.724016

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