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Defective migration of neural precursors in the developing gut leads to intestinal aganglionosis (Hirschsprung's disease). To overcome limits associated with the current surgical treatment of this common birth disorder we are exploring regenerative tissue repair of the gut using ES cell-derived neural cells. During embryonic development, the enteric nervous system (ENS) is derived from neural crest cells. Bone morphogenetic proteins (BMPs) are known to regulate important aspects of ENS progenitor differentiation and migration. PSA-NCAM is regarded as a key modulator of neural migration. Recently, BMPs have been shown to exhibit neural crest-inducing properties in embryonic stem cell-derived neural precursors. Immature BMP-induced peripheral neurons exhibit strong PSA-NCAM expression. Exploiting these, we combined PSA-NCAM immunopanning and BMP treatment to enrich populations of peripheral neuronal precursors. Upon in vitro differentiation these cells segregate into GABAergic, glutamatergic, serotoninergic, cholinergic and calretinin-positive phenotypes. After in vitro transplantation they incorporate into organotypic cultures of the mouse gut, where they acquire a cholinergic, peripherin-positive fate. Transplanted PSA-NCAM expressing ES cell-derived neural cells integrate as single cells rather than as cell clusters. This might be beneficial for functional integration of donor cells. The data indicate that ES cell-derived peripheral neural precursors might serve as a donor source for enteric nervous system repair. [ABSTRACT FROM AUTHOR]