Generation of region-specific neural cells from Embryonic Stem Cells

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Recently significant progress has been made in the molecular understanding of neural induction in Xenopus and Drosophila. By contrast, relatively little is known about molecular mechanisms of mammalian neural induction and generation of diverse neurons. Using mammalian Embryonic Stem (ES) cells, we are studying these issues.To begin with, we established an in vitro experimental system that induces neural differentiation of mouse and primate ES cells. Using co-culture system, we have identified neural inducing activity of ES cells in some stromal cells and named this activity Stromal Cell-Derived Inducing Activity (SDIA). Especially PA6 cells (stromal cells derived from skull bone marrow)efficiently (>90%) induce neural differentiation of ES cells.We next analyzed regional identities of SDIA-induced neural cells. SDlA-treated ES cells express forebrain, midbrain and hindbrain markers but not spinal cord markers. They express a variety of dorsal-ventral neural markers in terms of dorsal-ventral axis.Finally, we examined the capacity of SDIA-treated ES cells to generate a wide variety of neural cell types. Retinoic Acid modified SDIA-treated ES cells into the caudal direction. Shh suppressed dorsal neural markers and induce ventral Central Nervous System tissues, such as motor neurons and floor plate cells. BMP4 suppressed ventral neural markers and induced dorsal and neural crest markers. Thus SDIA-treated ES cells have the competence to respond to patterning factors, such as Retinoic Acid, Shh and BMP4, and can be modified to region-specific neural cells.