The study describes a mechanism by which progenitor cells of the central nervous system (CNS) can give rise to non-neural derivatives through spontaneous fusion with pluripotent embryonic stem (ES) cells. When CNS cells are co-cultured with ES cells, undifferentiated stem cells are recovered in which the brain cell genome has undergone epigenetic reprogramming. These cells carry a transgenic marker and chromosomes from the ES cells, indicating that the altered phenotype arises from spontaneous hybrid cell formation rather than direct conversion of brain cells to ES cells. The tetraploid hybrids exhibit full pluripotent characteristics, including multilineage contribution to chimaeras. The study suggests that transdetermination resulting from cell fusion could explain many observations previously attributed to intrinsic plasticity of tissue stem cells. The research also investigates the capacity of hybrid cells to contribute to embryonic development through blastocyst injection. Contributions to fetal tissues were detected in 8 of 23 transferred embryos by β-galactosidase staining. The contributions were modest and uneven, but this is expected due to competitive overgrowth of tetraploid hybrid cells by diploid host cells. Interestingly, one live-born mouse showed overt coat-color chimaerism, indicating that hybrid cells can contribute to multiple tissues. The study further examines whether similar fusion events can occur with cells isolated from adult brain. It shows that spontaneous fusion between mammalian cells can occur, and that this phenomenon is not dependent on the use of specific ES cell lines. The findings challenge the concept of progressive lineage restriction during development and suggest that the ability of cells from one tissue to generate progeny of another type may be explained by spontaneous hybrid formation. The study also explores the role of Shaggy/GSK3 in regulating Hedgehog signaling by modulating the processing of Cubitus interruptus (Ci). GSK3 phosphorylates Ci, which targets it for proteolytic processing, while Hedgehog signaling opposes this by promoting dephosphorylation of Ci. This regulation is crucial for proper development and patterning in Drosophila. The findings highlight the complex interplay between signaling pathways in developmental biology and the importance of understanding the mechanisms that govern cell fate determination.The study describes a mechanism by which progenitor cells of the central nervous system (CNS) can give rise to non-neural derivatives through spontaneous fusion with pluripotent embryonic stem (ES) cells. When CNS cells are co-cultured with ES cells, undifferentiated stem cells are recovered in which the brain cell genome has undergone epigenetic reprogramming. These cells carry a transgenic marker and chromosomes from the ES cells, indicating that the altered phenotype arises from spontaneous hybrid cell formation rather than direct conversion of brain cells to ES cells. The tetraploid hybrids exhibit full pluripotent characteristics, including multilineage contribution to chimaeras. The study suggests that transdetermination resulting from cell fusion could explain many observations previously attributed to intrinsic plasticity of tissue stem cells. The research also investigates the capacity of hybrid cells to contribute to embryonic development through blastocyst injection. Contributions to fetal tissues were detected in 8 of 23 transferred embryos by β-galactosidase staining. The contributions were modest and uneven, but this is expected due to competitive overgrowth of tetraploid hybrid cells by diploid host cells. Interestingly, one live-born mouse showed overt coat-color chimaerism, indicating that hybrid cells can contribute to multiple tissues. The study further examines whether similar fusion events can occur with cells isolated from adult brain. It shows that spontaneous fusion between mammalian cells can occur, and that this phenomenon is not dependent on the use of specific ES cell lines. The findings challenge the concept of progressive lineage restriction during development and suggest that the ability of cells from one tissue to generate progeny of another type may be explained by spontaneous hybrid formation. The study also explores the role of Shaggy/GSK3 in regulating Hedgehog signaling by modulating the processing of Cubitus interruptus (Ci). GSK3 phosphorylates Ci, which targets it for proteolytic processing, while Hedgehog signaling opposes this by promoting dephosphorylation of Ci. This regulation is crucial for proper development and patterning in Drosophila. The findings highlight the complex interplay between signaling pathways in developmental biology and the importance of understanding the mechanisms that govern cell fate determination.