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