Tlx Promotes Stroke-Induced Neurogenesis and Neuronal Repair in Young and Aged Mice

Stroke is one of the leading causes of chronic disability in humans. It has been proposed that the endogenous neural stem/progenitor cells generate new neurons in the damaged area. Still, the contribution of these cells is negligible because a low number of newborn mature neurons are formed. <i>Tlx</i> conventional knock-out mice, <i>Tlx</i>-CreERT2 mice, and <i>Tlx</i>-overexpressing (<i>Tlx</i>-OE) mice were specifically chosen for their unique genetic characteristics, which were crucial for the experiments. Permanent and transient middle cerebral artery occlusion was used to induce stroke in the mice. Immunostainings for doublecortin and GFP/BrdU/NeuN were performed to study neurogenesis and fate mapping. The rotarod test was performed to assess motor deficits. Here, we show that stroke-induced neurogenesis is dramatically increased with the additional expression of two copies of the nuclear receptor-coding gene <i>tailless</i> (<i>Tlx</i>, also known as <i>Nr2e1</i>), which has been shown to be a master regulator of subventricular zone (SVZ) neural stem cells (NSCs). We show that <i>Tlx</i> expression is upregulated after stroke, and stroke-induced neurogenesis is blocked when <i>Tlx</i> is inactivated. <i>Tlx</i> overexpression in NSCs leads to massive induction of neurogenesis via stroke. More newborn mature neurons are formed in <i>Tlx</i>-overexpressing mice, leading to improved coordination and motor function recovery. Most importantly, we also demonstrate that this process is sustained in aged mice, where stroke-induced neurogenesis is nearly undetectable in wild-type animals. This study provides the first stem cell-specific genetic evidence that endogenous NSCs can be exploited by manipulating their master regulator, <i>Tlx</i>, and thus suggests a novel therapeutic strategy for neuronal repair.