Tle4 controls both developmental acquisition and early post-natal maturation of corticothalamic projection neuron identity

• Published in: Cell reports (Cambridge) Vol. 42; no. 8; p. 112957
• Main Authors: Galazo, Maria J., Sweetser, David A., Macklis, Jeffrey D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.08.2023; Elsevier
• Subjects: Animals; Cerebral Cortex; corticospinal neurons; corticothalamic neurons; CP: Developmental biology; CP: Neuroscience; epigenetic regulation; Female; Fezf2; Interneurons; Mice; neuron identity acquisition; neuron identity stability; Neurons - metabolism; Pregnancy; subcerebral projection neurons; Tle4; Tle4; neuron identity acquisition; subcerebral projection neurons; corticospinal neurons; CP: Neuroscience; corticothalamic neurons; neuron identity stability; CP: Developmental biology; Fezf2; epigenetic regulation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112957

Identities of distinct neuron subtypes are specified during embryonic development, then maintained during post-natal maturation. In cerebral cortex, mechanisms controlling early acquisition of neuron-subtype identities have become increasingly understood. However, mechanisms controlling neuron-subtype identity stability during post-natal maturation are largely unexplored. We identify that Tle4 is required for both early acquisition and post-natal stability of corticothalamic neuron-subtype identity. Embryonically, Tle4 promotes acquisition of corticothalamic identity and blocks emergence of core characteristics of subcerebral/corticospinal projection neuron identity, including gene expression and connectivity. During the first post-natal week, when corticothalamic innervation is ongoing, Tle4 is required to stabilize corticothalamic neuron identity, limiting interference from differentiation programs of developmentally related neuron classes. We identify a deacetylation-based epigenetic mechanism by which TLE4 controls Fezf2 expression level by corticothalamic neurons. This contributes to distinction of cortical output subtypes and ensures identity stability for appropriate maturation of corticothalamic neurons. [Display omitted] •Tle4 promotes CThPN identity and blocks SCPN identity in early-born cortical neurons•Tle4 is necessary to maintain CThPN identity during circuit maturation•TLE4-FEZF2 complex regulates Fezf2 expression in developing CThPN•TLE4-FEZF2 regulates corticofugal subtypes distinction and developmental maturation of CThPN Corticothalamic neurons and subcerebral projection neurons are distinct neuron subtypes that constitute the output of the cerebral cortex. Galazo et al. show that Tle4 promotes acquisition of corticothalamic identity, suppresses subcerebral projection neuron identity in early-born corticofugal neurons during embryonic development, and stabilizes corticothalamic identity during early post-natal maturation.