Tle4 controls both developmental acquisition and postnatal maintenance of corticothalamic projection neuron identity

Identities, circuitry, and function of distinct neuron subtypes are specified during embryonic development, then maintained during postnatal maturation and potential plasticity. Mechanisms that control early acquisition of neuron subtype identities, encompassing circuitry and function, in the cerebral cortex have become increasingly understood. However, mechanisms controlling maintenance of identity, and accompanying regulation of plasticity, are largely unexplored and unknown. Here, we identify two novel functions of the co-repressor Tle4 in both acquisition and maintenance of neuron subtype identity of corticothalamic projection neurons. Embryonically, Tle4 promotes acquisition of corticothalamic molecular and cellular identity, and blocks emergence of core characteristics of subcerebral / corticospinal projection neuron identity, including morphology, gene expression, axonal connectivity, and circuitry. Postnatally, Tle4 is required to maintain corticothalamic molecular and projection identity during circuit maturation, avoiding potentially disruptive plasticity, but also limiting potentially beneficial plasticity. We identify an epigenetic mechanism by which TLE4 controls the activation state of loci regulating the level of Fezf2 expression by corticothalamic neurons during embryonic and postnatal development. This mechanism contributes importantly to distinction of cortical output (corticofugal) subtypes, and ensures appropriate maturation and maintenance of CThPN. HighlightsO_LITle4 promotes CThPN identity and blocks SCPN identity in early-born cortical neurons C_LIO_LITle4 is necessary to maintain CThPN identity during circuit maturation C_LIO_LITLE4-FEZF2 complex epigenetically regulates Fezf2 expression in developing CThPN C_LIO_LITLE4-FEZF2 regulates corticofugal subtypes distinction and maturation of CThPN C_LI