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

In addition to their cell-autonomous activities, a number of homeoprotein transcription factors transfer between cells and regulate gene expression, protein translation and chromatin organization in a non-cell autonomous way. ENGRAILED-1 is one such homeoprotein and is 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 and induces the loss of neuromuscular strength and of some α-motoneurons. A similar but stronger phenotype is observed in the Engrailed-1 heterozygote mouse, confirming that ENGRAILED-1 exerts a non-cell autonomous 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 neuromuscular weakness. Midbrain dopaminergic neurons express Engrailed-1 and, similarly to spinal cord α-motoneurons, degenerate in the heterozygote. The identification of genes with modified expression in Engrailed-1 heterozygote versus wild-type midbrain neurons that are also expressed in spinal cord motoneurons and with modified expression in the main familial ALS forms, led us to identify SQTSM1/p62 expression as an age marker in spinal cord motoneurons. The increase of SQTSM1/p62 expression is accelerated in the Engrailed-1 heterozygote and upregulated upon extracellular ENGRAILED-1 neutralization. We propose that ENGRAILED-1 is a regulator of motoneuron ageing with non-cell autonomous neurotrophic activity.