biostudies-literatureLebœuf MEuropean Research CouncilAssociation Nationale de la Recherche et de la Technologiee56525https://www.ebi.ac.uk/biostudies/studies/S-EPMC10398658biostudies-literatureUnknown24(8)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 that synapse on α-motoneurons. Neutralizing extracellular ENGRAILED-1 by expressing a secreted single-chain antibody blocks its capture by spinal motoneurons resulting in α-motoneuron 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 α-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 α-motoneurons, degenerate in the heterozygote. We identify genes expressed in spinal cord motoneurons whose expression changes in mouse Engrailed-1 heterozygote midbrain neurons. Among these, p62/SQSTM1 shows increased expression during aging in spinal cord motoneurons in the Engrailed-1 heterozygote and upon extracellular ENGRAILED-1 neutralization. We conclude that ENGRAILED-1 might regulate motoneuron aging and has non-cell-autonomous neurotrophic activity.EMBO reportsENGRAILED-1 transcription factor has a paracrine neurotrophic activity on adult spinal α-motoneurons.PMC103986582017/0488339379Lebœuf MPeze-Hedsieck EVargas-Abonce SEProchiantz AJimenez-Alonso LMoya KLDupont EfalseENGRAILED-1 transcription factor has a paracrine neurotrophic activity on adult spinal α-motoneurons.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 that synapse on α-motoneurons. Neutralizing extracellular ENGRAILED-1 by expressing a secreted single-chain antibody blocks its capture by spinal motoneurons resulting in α-motoneuron 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 α-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 α-motoneurons, degenerate in the heterozygote. We identify genes expressed in spinal cord motoneurons whose expression changes in mouse Engrailed-1 heterozygote midbrain neurons. Among these, p62/SQSTM1 shows increased expression during aging in spinal cord motoneurons in the Engrailed-1 heterozygote and upon extracellular ENGRAILED-1 neutralization. We conclude that ENGRAILED-1 might regulate motoneuron aging and has non-cell-autonomous neurotrophic activity.2023-01-01T00:00:00Z2023 Aug2025-07-02T03:04:19.342Z2025-04-06T17:46:03.623ZS-EPMC103986583753458110.15252/embr.202256525