Input-output decoding of oscillatory gene expression during neurogenesis

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Gene expression oscillations in a short time scale of 2-5hrs are functionally important for cell-state transitions but the downstream targets and the decoding mechanisms are not understood. Here, we will use innovative combination of single cell live imaging of endogenous protein-fusion-reporters with the power of manipulating dynamics to address these questions. We will focus on the dynamics of a transcription factor Neurogenin2, Ngn2 and its downstream target, NeuroD. Our model system will be in vitro neural differentiation with well-established published protocols of established lines of human Embryonic Stem Cells (hESCs) , along a ventral spinal cord neuronal pathway, for live imaging and molecular studies. In the first aim we will ask how Ngn2 oscillations generated and interpreted in the dynamics of NeuroD. Since Ngn2 shows dynamical expression, in the second aim, we will manipulate the Ngn2 dynamics and ask what genes are differentially activated by oscillatory versus sustained Ngn2 expression. Our research will dissect the sequence of molecular events that lead to cell-state transitions and in doing so will provide mechanistic insight into a fundamental biological process, the progenitor to differentiated cell transition, that underlies development, regeneration and cancer.