The Collaborative Regulation of Cortical Neuron Subtype Specification by TLE4 and FEZF2

Projection neuron subtype identities in the cerebral cortex are established through the expression of pan-cortical and subtype-specific effector genes, which execute terminal differentiation programs that bestow neurons with a glutamatergic neuron phenotype and subtype-specific morphology, physiology, and axonal projections. Whether pan-cortical glutamatergic and subtype-specific characteristics are regulated by the same genes or controlled by distinct programs remains largely unknown. Here, I show that the transcriptional corepressor, TLE4, is expressed specifically in postmitotic corticothalamic projection neurons, where it functions to regulate the molecular, dendritic, and electrophysiological characteristics unique to corticothalamic neurons. I also demonstrate that TLE4 directly interacts with the forebrain embryonic zinc finger protein, FEZF2, within corticothalamic projection neurons to facilitate the transcriptional repression of subcerebral projection neuron identity. Through the utilization of our novel Fezf2-Bac-EnR transgenic mouse line, I was then able rescue the molecular defects of corticothalamic neurons in the cortex of Tle4 knockout mice and restore the dendritic and electrophysiological characteristics of theses neurons. Overall, the work presented provides an in-depth investigation into the transcriptional regulation of subtype-specific cortical projection neuron identity by Tle4 and Fezf2, thereby contributing novel insight into our current understanding of mammalian cortical development