Transcriptional repression by FEZF2 restricts alternative identities of cortical projection neurons.

Jeremiah Tsyporin,Daisy Gallardo,Nenad Sestan,Susan K Mcconnell,Amr Makhamreh,Antoine Nehme,Thomas Finn,Bin Chen,Xiaokuang Ma,Solomon Katzman,Shenfeng Qiu,Zhengang Yang,Jacqueline M Roberts,Guoping Liu,Liora Huebner,David Tastad

doi:10.1016/j.celrep.2021.109269

Abstract

SUMMARYProjection 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.

Highlights

Projection neuron subtype identities in the developing cerebral cortex are established by expressing pan-cortical and subtype-specific genes, which execute terminal differentiation programs and bestow neurons with a glutamatergic phenotype and subtype-specific morphology, physiology, and axonal projections
Whether similar mechanisms are utilized in developing mammalian brains is unknown, except the corticospinal motor neurons (CSMNs), a subset of subcerebral projection neurons specified by the transcriptional regulator FEZF2 (Lodato et al, 2014)
Our results suggest that distinct genetic programs act sequentially to regulate the differentiation of cortical projection neurons, with genes expressed in progenitor cells specifying the pan-cortical glutamatergic phenotype, and subtype-specifying transcription factors functioning in postmitotic cells to selectively repress the expression of genes associated with alternate subtype identities

Summary

Introduction

Projection neuron subtype identities in the developing cerebral cortex are established by expressing pan-cortical and subtype-specific genes, which execute terminal differentiation programs and bestow neurons with a glutamatergic phenotype and subtype-specific morphology, physiology, and axonal projections. Whether the pan-cortical glutamatergic phenotype and subtype-specific characteristics are regulated by the same genetic program or controlled by distinct genes remains largely unknown. Whether similar mechanisms are utilized in developing mammalian brains is unknown, except the corticospinal motor neurons (CSMNs), a subset of subcerebral projection neurons specified by the transcriptional regulator FEZF2 (Lodato et al, 2014). Determining the molecular mechanisms underlying the differentiation of these neuronal subtypes is essential for understanding the regulatory logic of cell fate specification in the neocortex

Results

Discussion

Conclusion