Neurons generated by mouse ES cell with hippocampal or cortical identity display distinct projection patterns when co-transplanted in the adult brain

The capability of generating neural precursor cells with distinct types of regional identity in vitro has recently opened new opportunities of cell replacement in animal models of neurodegenerative diseases. By manipulating Wnt and BMP signaling, we steered the differentiation of mouse ES cells towards isocortical or hippocampal molecular identity. These two types of cells showed different degrees of axonal outgrowth and targeted different regions when co-transplanted in the healthy or lesioned isocortex, or in hippocampus. In hippocampus, only precursor cells with hippocampal molecular identity were able to extend projections, contacting CA3. Conversely, isocortical-like cells were capable of extending long-range axonal projections only when transplanted in motor cortex, sending fibers toward both intra- and extra-cortical targets. Ischemic damage induced by photothrombosis greatly enhanced the capability of isocortical-like cells to extend far-reaching projections. Our results indicate that neural precursors generated by ES cells carry intrinsic signals specifying axonal extension in different environments. Gene expression was evaluated in ESC-derived neurons at 16 days of in vitro differentiation upon treatment at different times with Wnt and BMP inhibitors or WNT; agonist global gene expression profiles were compared to E15 mouse embryo cortex, hippocampus, ventral telencephalon and midbrain.