UC Santa Cruz

Projection neurons underly cortical computation and are necessary for proper cortical function. Understanding how these cell types arise is a central question in neuroscience and has wide-ranging implications for treating brain diseases. Genes encoding for transcription factors or chromatin remodeling proteins have been identified that are necessary for generating projection neuron cell types in the cerebral cortex. Exactly how they function is unknown. Using genetically engineered mouse models combined with immunohistochemistry, bulk and single-cell RNA sequencing, chromatin profiling, circuit tracing, and electrophysiology, this work uncovers the molecular mechanisms by which the transcription factors Fezf2, Satb2, and the transcriptional corepressor Tle4, specify cell fate in the developing cerebral cortex. Fezf2 specifies cell fate by functioning as a selective repressor. It regulates subtype-specific identities of corticothalamic and subcerebral neurons by selectively repressing the expression of genes inappropriate for each neuronal subtype. Tle4 works collaboratively with Fezf2 in layer 6 to inhibit layer 5 subcerebral neuronal genes. On the other hand, Satb2 is involved in gene activation and repression; these functions are likely mediated by interactions with ATP-dependent chromatin remodeling complexes. This work also demonstrates that Satb2 dosage affects cortical development, shedding light on the etiology of patients with a mutant SATB2 allele.Fezf2, Tle4, and Satb2 all function to specify subtype identity in postmitotic neurons. These results indicate that a cortical glutamatergic identity is specified by progenitor cells, but subtype-specific identity is achieved through postmitotic fate refinement.