ENGRAILED-1 transcription factor has a paracrine neurotrophic activity on adult spinal α-motoneurons

EMBO Rep. 2023 Aug 3;24(8):e56525. doi: 10.15252/embr.202256525. Epub 2023 Jul 6.


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.

Keywords: ALS; ENGRAILED1; Motoneurons; Neurodegeneration; Paracrine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Interneurons / metabolism
  • Mice
  • Motor Neurons* / metabolism
  • Spinal Cord / metabolism
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism


  • Transcription Factors
  • Homeodomain Proteins