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Sex-Biased Transcription in Early Postnatal Layer 2/3 Cortical Neurons: Interplay Between Sex and Cux1/2 Mutations

ABSTRACT: Despite many neurodevelopmental disorders (NDDs) exhibiting pronounced sex differences, the role of sex in shaping the genetic regulation of the brain remains barely explored. Brain development relies on a precise control of gene expression across time and disruptions in this process, especially during critical periods, can result in NDDs. In the neocortex, layer (L) 2/3 excitatory pyramidal neurons stand out for integrating information across cortical areas and hemispheres. Here, we show a transient window of sex-biased gene expression of L2/3 neurons at postnatal day 4 (P4), mainly characterized by autosomal genes. Loss-of-function experiments targeting Cux1 and Cux2, key transcription factors in L2/3 development, lead to sex-dependent transcriptional deregulation in these neurons, with a significant male-biased sensitivity. Moreover, differentially expressed genes shift substantially between developmental stages, reflecting the dynamic regulation of Cux-mediated gene expression. Overall, our study identifies P4 as a key determinant of early sex differences and highly vulnerable stage for the emergence of NDDs, and highlights the importance of sex-specific analyses for understanding brain development and disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE310138 | GEO | 2026/05/20

REPOSITORIES: GEO

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Project description:Humans exhibit sex differences in the prevalence and presentation of many psychiatric and neurodevelopmental conditions, including Alzheimer’s disease, autism spectrum disorder (ASD), and schizophrenia; however, the ‘omic’, developmental, and environmental underpinnings of these conditions remain elusive. To illuminate these mechanisms and their interactions, and to identify potential therapies, we need large, sex-specific neurobiological data sets from model organisms whose brains exhibit similar characteristics to those of humans, including comparable sex differences. Among existing models, the rhesus macaque is likely to have the greatest translatability; however, comprehensive analyses of brain sex differences in this species are necessary to demonstrate their relevance to sex-biased human conditions. We present an in-depth investigation of sex differences in the rhesus macaque brain transcriptome (RNA-seq) across 527 samples of 15 regions from 36 free-ranging adult individuals (20F/16M), representing the largest collection of bulk brain gene expression data for this species. We identified hundreds of sex-biased genes throughout the rhesus macaque brain, most of which were shared across regions, suggesting convergent regulatory mechanisms. Similar to studies of human brains, these sex-biased genes are regulated by sex hormones and transcription factors that interact with these hormones, male-biased genes are associated with multiple sex-biased human neurological conditions (e.g., ASD, schizophrenia) and energy metabolism, and female-biased genes are associated with the immune response. We also accurately predicted sex from a relatively small number of genes per region and found that, among genes reported to escape X chromosome inactivation in humans, similar genes are the most predictive of sex both across human tissues and in this dataset. Finally, we demonstrated that sex-biased genes exhibit characteristics that facilitate rapid evolution, including a tendency to be located on the sex chromosomes, more tissue-specific expression, and higher genetic variance for expression. Overall, these findings suggest that the rhesus macaque may be an appropriate model for sex-biased human neurological conditions.

Dataset Information

Sex-Biased Transcription in Early Postnatal Layer 2/3 Cortical Neurons: Interplay Between Sex and Cux1/2 Mutations

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