A dual enhancer-attenuator element ensures transient Cdx2 expression during mouse posterior body formation

During development, cells express precise gene expression programs to assemble the trunk of the body plan. Appropriate control over the duration of the transcription factor Cdx2 is critical to achieve this outcome, yet how cells control the onset, maintenance, or termination of Cdx2 has remained unclear. Here, we delineate the cis-regulatory logic orchestrating dynamic Cdx2 expression in mouse caudal epiblast progenitors and their derivatives. Combining CRISPR-mediated deletion of regulatory elements with in vitro models and in vivo validation, we demonstrate that distinct enhancers and a repressive element embedded at the Cdx2 locus act sequentially to drive transient Cdx2 expression. We pinpoint an "attenuator": a minimal region relying on a nuclear receptor to extinguish Cdx2. Changing this single motif converts the attenuator to an enhancer with the opposite regulatory behavior. Our findings establish a dual cis-regulatory logic ensuring precise spatiotemporal control over gene expression for vertebrate body patterning.