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

TY - JOUR

T1 - Lmo4 synergizes with Fezf2 to promote direct in vivo reprogramming of upper layer cortical neurons and cortical glia towards deep layer neuron identities

AU - Felske, Torsten

AU - Tocco, Chiara

AU - Peron, Sophie

AU - Harb, Kawssar

AU - Alfano, Christian

AU - Galante, Chiara

AU - Berninger, Benedikt

AU - Studer, Michele

N1 - Funding Information: Funding: This work was funded by an AFM-Telethon grant (20899 to MS), by the French Government (National Research Agency, ANR) through the ‘Investments for the Future’ programs LABEX SIGNALIFE (ANR-11-LABX-0028-01 and IDEX UCAJedi ANR-15-IDEX-01 to MS), by an ERA-NET Neuron grant (Brain4Sight) (ANR-21-NEU2-0003-03 to MS; 01EW2202 to BB); by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (101021560, IMAGINE to BB), by the Wellcome Trust (206410/Z/17/Z to BB), by the German Research Foundation (BE 4182/11-1, 357058359 to BB), by the research initiative of Rheinland-Pfalz at the Johannes Gutenberg University Mainz (ReALity to BB); by a SIGNALIFE Ph.D. contract to TF and by the Inneruniversitäre Forschungsförderung Stufe I of the Johannes Gutenberg University Mainz to SP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2023 Felske et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,provided the original author and source are credited.

PY - 2023/8/8

Y1 - 2023/8/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85167371626&partnerID=8YFLogxK

U2 - 10.1371/journal.pbio.3002237

DO - 10.1371/journal.pbio.3002237

M3 - Article

SN - 1544-9173

VL - 21

JO - PLoS Biology

JF - PLoS Biology

IS - 8 August

M1 - e3002237

ER -