A Molecular Switch Regulating Neurogenesis

Inventors: Fred Gage and Tomoko Kuwabara
Potential Uses: CNS, Modulation of Gene Expression
A "master switch" that determines whether the genetic program that mediates neural differentiation is repressed or activated

During the initiation of neurogenesis, neural stem cells exit the undifferentiated state and commit to becoming neuroblasts, the first stage in the differentiation toward neurons. Previous efforts have been unsuccessful in revealing the mechanism which controls this neural phenotype development.

This invention describes the transcriptional regulatory mechanism that functions as a "master switch" in neural development, determining whether the genetic program that mediates neural differentiation is repressed or activated. The mechanism relates to recently identified LEF/Sox overlapping response elements within the upstream regulatory sequences of neural specific genes such as NeuroD1. Activation via this molecular switch induces neurogenesis in neural stem cells and controls the irreversible commitment step from stem cells to neuroblasts.

Compositions and methods are described for directing neural specific expression of polynucleotide sequences. These can be used to modulate differentiation of stem cells into neural lineage cells, or, for the prevention/inhibition of differentiation-for example, to maintain a stem cell in an undifferentiated state. New screening methods have also been identified that are particularly suited for high-throughput evaluation of large composition libraries to identify agents that modulate differentiation of stem cells.