<i>Lin28a/let-7</i> pathway modulates the <i>Hox</i> code via <i>Polycomb</i> regulation during axial patterning in vertebrates.

Abstract

The body plan along the anteroposterior axis and regional identities are specified by the spatiotemporal expression of <i>Hox</i> genes. Multistep controls are required for their unique expression patterns; however, the molecular mechanisms behind the tight control of <i>Hox</i> genes are not fully understood. In this study, we demonstrated that the <i>Lin28a</i>/<i>let-7</i> pathway is critical for axial elongation. <i>Lin28a</i>^-/- mice exhibited axial shortening with mild skeletal transformations of vertebrae, which were consistent with results in mice with tail bud-specific mutants of Lin28a. The accumulation of <i>let-7</i> in <i>Lin28a</i>^-/- mice resulted in the reduction of PRC1 occupancy at the <i>Hox</i> cluster loci by targeting <i>Cbx2</i>. Consistently, Lin28a loss in embryonic stem-like cells led to aberrant induction of posterior <i>Hox</i> genes, which was rescued by the knockdown of <i>let-7</i>. These results suggest that the <i>Lin28</i>/<i>let-7</i> pathway is involved in the modulation of the '<i>Hox</i> code' via <i>Polycomb</i> regulation during axial patterning.