Transcriptional repression by FEZF2 restricts alternative identities of cortical projection neurons
Jeremiah Tsyporin, David Tastad, Xiaokuang Ma, Antoine Nehme, Thomas S. Finn, Liora Huebner, Guoping Liu, Daisy Gallardo, Amr Makhamreh, Jacqueline M. Roberts, Solomon Katzman, Nenad Šestan, Susan K. McConnell, Zhengang Yang, Shenfeng Qiu, Bin Chen
Abstract
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.