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.
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.
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