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bioRxiv · 10.1101/2025.10.19.683266

Sex-biased transcriptome in embryonic mouse cortices under Pax6 haploinsufficiency highlights Pbdc1 as a candidate regulator

Manabe, S.·Ochi, S.·Kikkawa, T.·Naher, S.·Saeki, M.·Yamada, K.·Kosako, H.·Kishi, Y.·Sawasaki, T.·Osumi, N.
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Abstract

Mutations in Pax6, encoding a transcription factor essential for brain patterning and neurogenesis, have been linked to female-biased cortical malformations and behavioral abnormalities, yet the molecular basis remains unclear. Here we show that Pax6 haploinsufficiency (Sey/+) produces more pronounced sex-biased alterations in the transcriptomes and cytoarchitecture of embryonic mouse cortices than those in wild-type and homozygous mutants (Sey/Sey). Pbdc1, a previously uncharacterized X-linked gene implicated in autism, is selectively upregulated in Sey/+ females and proximity-dependent protein-protein interaction analysis reveals Pbdc1 interacts with RNA-splicing factors. Moreover, Pbdc1 overexpression reduces intermediate progenitor cells in the developing cortex. ChIP-qPCR further demonstrates Pax6 and BAF occupancy at the Pbdc1 promoter in WT embryos of both sexes and CUT&Tag shows H3K4me3 elevation selectively in Sey/+ females. Our findings indicate that partial loss of Pax6 shapes the embryonic cortical transcriptomes and cytoarchitecture in a sex-dependent manner and highlight Pbdc1 as a candidate regulator of sex-biased corticogenesis.

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Manabe, S., Ochi, S., Kikkawa, T., Naher, S., Saeki, M., Yamada, K., Kosako, H., Kishi, Y., Sawasaki, T., Osumi, N.. 2025-10-19. Sex-biased transcriptome in embryonic mouse cortices under Pax6 haploinsufficiency highlights Pbdc1 as a candidate regulator. https://doi.org/10.1101/2025.10.19.683266

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