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[0001] The present invention relates to compositions and methods for obtaining a corticospinal upper motor neuron from a neural stem cell comprising the use of a CB<1>cannabinoid receptor agonist, or the use of an inhibitor of an endocannabinoid-degrading enzyme, or the modification of a neural stem cell to decrease the expression of an endocannabinoid-degrading enzyme under basal levels or to increase the expression of the CB<1>cannabinoid receptor above basal levels. The invention also relates to the corticospinal upper motor neurons obtained and uses thereof.

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1. Anin vitro method for obtaining a corticospinal upper motor neuron from a neural stem cell, wherein said method comprises contacting a neural stem cell under conditions adequate for increasing the signal mediated by the CB<1> cannabinoid receptor in said cell and under conditions to promote dorsalization of said cell. 2. The method according to claim 1, wherein the increase in the signal mediated by the CB<1> cannabinoid receptor involves contacting said neural stem cell with a CB<1> cannabinoid receptor agonist and/or modifying said neural stem cell to increase the expression of the CB<1> cannabinoid receptor above basal levels and/or increasing in the cell the activity of an endocannabinoid-synthesizing enzyme above basal levels. 3. The method according to claim 2, wherein the CB<1> cannabinoid receptor agonist is selected from the group consisting of HU-210 and arachidonyl-2'-chloroethylamide (ACEA). 4. The method according to any of claims 1 to 3, wherein the increase in the signal mediated by the CB<1> cannabinoid receptor involves decreasing in the cell the activity of an endocannabinoid-degrading enzyme, wherein preferably the endocannabinoid-degrading enzyme is selected from the group consisting of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). 5. The method according to claim 4, wherein said decrease in the activity of an endocannabinoid-degrading enzyme is carried out by modifying said cell with an agent which silences said enzyme and/or contacting a neural stem cell with an inhibitor of said endocannabinoid-degrading enzyme. 6. The method according to claim 5, wherein the inhibitor of monoacylglycerol lipase is JZL184 and/or the inhibitor of fatty acid amide hydrolase is URB597. 7. The method according to any of claims 1 to 6, wherein the conditions to promote dorsalization involve contacting said neural stem cell with a dorsalizing agent selected from: a) a sonic hedgehog inhibitor; and b) a Smad inhibitor. 8. The method according to claim 7, wherein the sonic hedgehog inhibitor is cyclopamine and/or the Smad inhibitor is selected from the group consisting of Noggin, SB431542 and a combination thereof. 9. A corticospinal upper motor neuron or a cell population comprising corticospinal upper motor neurons obtainable by a method according to any of claims 1 to 8. 10. A pharmaceutical composition comprising a corticospinal upper motor neuron or a cell population according to claim 9, and a pharmaceutically acceptable carrier. 11. Use of a corticospinal upper motor neuron or a cell population according to claim 9, for evaluating a biological, pharmacological and/or chemical product. 12. A corticospinal upper motor neuron or a cell population according to claim 9 or a pharmaceutical composition according to claim 10 for use in the treatment of a motor neurodegenerative disorder. 13. A composition comprising an agent capable of increasing the signal mediated by the CB<1> cannabinoid receptor in a neural stem cell and a further agent selected from: a) a sonic hedgehog inhibitor and b) a Smad inhibitor. 14. An isolated neural stem cell having a loss of the CB<1> cannabinoid receptor function or a population of neurons obtainable byin vitro differentiation from a neural stem cell having a loss of the CB<1> cannabinoid receptor function, wherein preferably the loss of the CB<1> cannabinoid receptor function is due to a partial or complete deletion or to a mutation in the CB<1> cannabinoid receptor. 15. Use of an isolated neural stem cell or a population of neurons according to claim 14 as a model for studying a motor neurodegenerative disorder or for screening for compounds useful in the treatment of a motor neurodegenerative disorder.

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