- Tsyporin, Jeremiah;
- Tastad, David;
- Ma, Xiaokuang;
- Nehme, Antoine;
- Finn, Thomas;
- Huebner, Liora;
- Liu, Guoping;
- Gallardo, Daisy;
- Makhamreh, Amr;
- Roberts, Jacqueline M;
- Katzman, Solomon;
- Sestan, Nenad;
- McConnell, Susan K;
- Yang, Zhengang;
- Qiu, Shenfeng;
- Chen, Bin
Projection neuron subtype identities in the cerebral cortex are established by expressing pan-cortical and subtype-specific effector genes that execute terminal differentiation programs bestowing 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, we show that FEZF2 functions as a transcriptional repressor, and it regulates subtype-specific identities of both corticothalamic and subcerebral neurons by selectively repressing expression of genes inappropriate for each neuronal subtype. We report that TLE4, specifically expressed in layer 6 corticothalamic neurons, is recruited by FEZF2 to inhibit layer 5 subcerebral neuronal genes. Together with previous studies, our results indicate that a cortical glutamatergic identity is specified by multiple parallel pathways active in progenitor cells, whereas projection neuron subtype-specific identity is achieved through selectively repressing genes associated with alternate identities in differentiating neurons.