Final Report Summary - HOMEOSIGN (HOMEOSIGN : Homeoprotein signaling during development and in the adult)
The project is based on a novel signaling pathway discovered by my laboratory. This pathway was revealed by the observation that homeoprotein (HP) transcription factors can transfer between cells to regulate transcription, translation and the chromatin epigenetic state in a direct non-cell autonomous way.
Thanks to the development of original genetic tools, in particular mice encoding inducible single-chain antibodies raised against 3 distinct HPs (OTX2, PAX6 and ENGRAILED), we demonstrated that extracellular PAX6 regulates Cajal-Retzius cell migration at Embryonic Day 11 in the mouse neuroepithelium.
We also used this technology to show that OTX2 transferred from the choroid plexus to parvalbumin interneurons of cerebral cortex layer IV regulates cerebral cortex plasticity, during post-natal development and in the adult. This has allowed us to identify the genetic pathways involved (OTX2 non-cell autonomous targets) and to cure experimental amblyopia in the mouse. The fact that OTX2 transfers throughout the cortex opens a possible novel understanding of how psychiatric diseases can be installed during development. The finding that OTX2 regulates plasticity not only in the visual cortex, but also in the auditory and medial prefrontal cortices, supports the latter hypothesis.
A last aspect of the study achieved during the grant period is the ability of the homeoprotein ENGRAILED-1 (EN1) to regulate the physiology and survival of mesencephalic dopaminergic (mDA) neurons, a class of cells that specifically degenerate in Parkinson disease. This has led to discover that EN1 is necessary to maintain the epigenetic state the chromatin during mDA neuron normal ageing or acute oxidative stress. RNA-seq experiments have allowed us to propose several mechanisms. One of them, of primary interest is the indirect (chromatin conformation) and direct (promoter binding) repression by EN1 of mobile genetic elements of the LINE-1 family. Indeed, LINE-1 is expressed in post-mitotic neurons (not necessarily reinserted into the genome) where it fulfils physio-pathological functions. Based on these results we have developed EN1 as a therapeutic protein in mouse and non-human primate models of Parkinson disease.
Thanks to the development of original genetic tools, in particular mice encoding inducible single-chain antibodies raised against 3 distinct HPs (OTX2, PAX6 and ENGRAILED), we demonstrated that extracellular PAX6 regulates Cajal-Retzius cell migration at Embryonic Day 11 in the mouse neuroepithelium.
We also used this technology to show that OTX2 transferred from the choroid plexus to parvalbumin interneurons of cerebral cortex layer IV regulates cerebral cortex plasticity, during post-natal development and in the adult. This has allowed us to identify the genetic pathways involved (OTX2 non-cell autonomous targets) and to cure experimental amblyopia in the mouse. The fact that OTX2 transfers throughout the cortex opens a possible novel understanding of how psychiatric diseases can be installed during development. The finding that OTX2 regulates plasticity not only in the visual cortex, but also in the auditory and medial prefrontal cortices, supports the latter hypothesis.
A last aspect of the study achieved during the grant period is the ability of the homeoprotein ENGRAILED-1 (EN1) to regulate the physiology and survival of mesencephalic dopaminergic (mDA) neurons, a class of cells that specifically degenerate in Parkinson disease. This has led to discover that EN1 is necessary to maintain the epigenetic state the chromatin during mDA neuron normal ageing or acute oxidative stress. RNA-seq experiments have allowed us to propose several mechanisms. One of them, of primary interest is the indirect (chromatin conformation) and direct (promoter binding) repression by EN1 of mobile genetic elements of the LINE-1 family. Indeed, LINE-1 is expressed in post-mitotic neurons (not necessarily reinserted into the genome) where it fulfils physio-pathological functions. Based on these results we have developed EN1 as a therapeutic protein in mouse and non-human primate models of Parkinson disease.