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bioRxiv · 10.1101/2022.08.16.504081

ENGRAILED-1 transcription factor exerts a paracrine neurotrophic activity on adult spinal cord α-motoneurons.

Leboeuf, M.·Vargas-Abonce, S. E.·Peze-Hedsieck, E.·Dupont, E.·Jimenez-Alonso, L.·MOYA, K. L.·Prochiantz, A.
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Abstract

Several homeoprotein transcription factors transfer between cells and regulate gene expression, protein translation, and chromatin organization in recipient cells. ENGRAILED-1 is one such homeoprotein expressed in spinal V1 interneurons synapsing on -motoneurons. Neutralizing extracellular ENGRAILED-1 by expressing a secreted single-chain antibody blocks its capture by spinal motoneurons resulting in -motoneurons loss and limb weakness. A similar but stronger phenotype is observed in the Engrailed-1 heterozygote mouse, confirming that ENGRAILED-1 exerts a paracrine neurotrophic activity on spinal cord -motoneurons. Intrathecal injection of ENGRAILED-1 leads to its specific internalization by spinal motoneurons and has long-lasting protective effects against neurodegeneration and weakness. Midbrain dopaminergic neurons express Engrailed-1 and, similarly to spinal cord -motoneurons, degenerate in the heterozygote. By identifying genes expressed in spinal cord motoneurons also showing modified expression in mouse Engrailed-1 heterozygote midbrain neurons, we identified p62/SQTSM1 as an age marker in spinal cord motoneurons with increased expression during aging, in the Engrailed-1 heterozygote and upon extracellular ENGRAILED-1 neutralization. We conclude that ENGRAILED-1 is a regulator of motoneuron ageing with non-cell autonomous neurotrophic activity.

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Leboeuf, M., Vargas-Abonce, S. E., Peze-Hedsieck, E., Dupont, E., Jimenez-Alonso, L., MOYA, K. L., Prochiantz, A.. 2022-08-16. ENGRAILED-1 transcription factor exerts a paracrine neurotrophic activity on adult spinal cord α-motoneurons.. https://doi.org/10.1101/2022.08.16.504081

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