Lmo4 synergizes with Fezf2 to promote direct in vivo reprogramming of upper layer cortical neurons and cortical glia towards deep-layer neuron identities

Abstract

In vivo direct neuronal reprogramming relies on the implementation of an exogenous transcriptional program allowing to achieve conversion of a particular neuronal or glial cell type towards a new identity. The transcription factor (TF) Fezf2 is known for its role in neuronal subtype specification of deep-layer (DL) subcortical projection neurons. High ectopic Fezf2 expression in mice can convert both upper-layer (UL) and striatal projection neurons into a corticofugal fate, even if at low efficiency. In this study, we show that Fezf2 synergizes with the nuclear co-adaptor Lmo4 to further enhance reprogramming of UL cortical pyramidal neurons into DL corticofugal neurons, at both embryonic and early postnatal stages. Reprogrammed neurons express DL molecular markers and project toward subcerebral targets, including thalamus, cerebral peduncle (CP), and spinal cord (SC). We also show that co-expression of Fezf2 with the reprogramming factors Neurog2 and Bcl2 in early postnatal mouse glia promotes glia-to-neuron conversion with partial hallmarks of DL neurons and with Lmo4 promoting further morphological complexity. These data support a novel role for Lmo4 in synergizing with Fezf2 during direct lineage conversion in vivo.

Programming of neural progenitors of the adult subependymal zone towards a glutamatergic neuron lineage by neurogenin 2

“…Also, dynamically regulated changes in the level of protein synthesis during lineage progression by miRNAs ( Baser et al., 2019 ) may render the competence of SEZ progenitors differentially susceptible to fate conversion. The failure of reprogramming at later stages of adult NSC lineage progression is even more intriguing given NEUROG2’s capacity to induce TBR2 and TBR1 in early postnatal cortical astrocytes in vitro ( Berninger et al., 2007a ; Heinrich et al., 2010 ) and to reprogram glia into glutamatergic neurons in vivo ( Felske et al., 2023 ; Gascon et al., 2016 ; Herrero-Navarro et al., 2021 ). The developmental window-specific actions of NEUROG2 on adult SEZ stem and progenitor cells exhibit remarkable parallelism as well as differences to that of the transcription factor FEZF2.…”

Rapid TetOn-mediated gene expression in neurons across the lifespan with uTTOP

“…The introduction of oriented bipolar electric fields and triple-electrode approaches has also made it possible to specifically target numerous brain areas using IUE (Baumgart and Baumgart, 2016;Carlson et al, 2011;dal Maschio et al, 2012). For these reasons, IUE remains a widely used technique for interrogating fundamental cell biology (Bandler et al, 2022;Chung et al, 2023;Ellender et al, 2019;Felske et al, 2023;Gonçalves et al, 2020;Huszár et al, 2022;Mavrovic et al, 2020;Paolino et al, 2023;Prieur et al, 2023;Tsai et al, 2020) and disease (Bennison et al, 2023;Braz et al, 2022;Cases-Cunillera et al, 2021;Druart et al, 2021;Sun et al, 2021) in the brain.…”