An essential role for CREB in mammalian somite morphogenesis.

摘要

The segmented body plan of vertebrates is pre-figured by a developmental process known as somitogenesis. Somites form rhythmically from the presomitic mesoderm (PSM) which is temporally linked to a "Segmentation clock"; a molecular oscillator that triggers waves of Notch activity (NICD) throughout the PSM. Once the clock crosses a determination front (Wavefront) set up by the FGF/Wnt morphogen gradients, the clock synchronizes a group of competent PSM cells to bud off and form a somite. Much remains to be understood of how the clock and wavefront are interlinked.;I have serendipitously found that the transcription factor CREB plays a novel role in mammalian somitogenesis. I show that activated CREB cycles in unison with NICD in the anterior PSM. Further, the oscillatory activities of CREB are governed by Wnt3a signaling. To directly test CREB function in somitogenesis, I employed a gene inactivation strategy to express a dominant negative agent to CREB in the mouse PSM. In these mutants, progression of somitogenesis is delayed and somites that do form are abnormal and fused, leading to skeletal dysplasia in neonates. To decipher the downstream mediators of CREB, I performed transcriptional profiling comparing control versus mutant PSM and identified differentially expressed genes. Surprisingly, several of them are linked to the Wnt and Notch signaling pathways. For example, Dll-1, a Notch ligand, display reduced expression and contains a CREB binding site in its promoter that confers in vivo CREB occupancy at this locus. I propose that CREB function is regulated by the Wnt3a wavefront and in turn CREB controls the Notch1 clock to direct somite patterning.