Epilepsy-associated FOXJ3 variants link a transcriptional program of the PTEN-mTOR pathway to neuronal specification and cortical lamination - PubMed
3 days ago
- #PTEN-mTOR pathway
- #FOXJ3
- #Epilepsy
- FOXJ3 pathogenic variants are identified in patients with autosomal dominant focal epilepsy and Focal Cortical Dysplasia (FCD).
- FOXJ3 expression declines sharply in neural progenitors after embryonic day 15.5 in the developing mouse cortex.
- Foxj3 knockdown in mouse brains via in utero electroporation impairs neuronal migration, disrupts cortical lamination, and alters neuronal specification, favoring upper-layer neuron production over deeper-layer neurons.
- ChIP-seq and scRNA-seq analyses reveal Pten as a key FOXJ3 target, with Pten overexpression rescuing cortical defects caused by FOXJ3 deficiency.
- FCD-associated FOXJ3 variants fail to upregulate Pten, leading to dysregulated mTOR signaling and enlarged neuronal soma, a hallmark of FCD.
- The findings suggest FOXJ3 mutations may cause epilepsy and FCD by disrupting a transcriptional program regulating the PTEN-mTOR pathway for neuronal specification and cortical lamination.