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

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 homeoproteins expressed in spinal V1 interneurons synapsing on a-motoneurons. Neutralizing extracellular ENGRAILED-1 by expressing a secreted single-chain antibody blocks its capture by spinal motoneurons resulting in a-motoneurons loss and muscular 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 a-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 a-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 SQTSM1/p62 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.

ORGANISM(S): Mus musculus (mouse)

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PROVIDER: S-BSST961 | biostudies-other |

REPOSITORIES: biostudies-other

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

Project description: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/SQTSM1 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.

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