RING1 contributes to early proximal-distal specification of the forelimb bud by restricting Meis2 expression

Polycomb group (PcG) proteins play a pivotal role in silencing development-related genes and help to maintain various stem and precursor cells and regulate their differentiation. PcG factors also regulate dynamic and complex regional specification, particularly in mammals, but this activity is mechanistically not well understood. In this study, we focused on proximal-distal (PD) patterning of the forelimb bud to elucidate how PcG factors contribute to a regional specification process that depends on developmental signals. Depletion of RING1 proteins, which are essential components of the Polycomb repressive complex-1 (PRC1), led to severe defects in forelimb formation along the PD axis. We show that preferential defects in early distal specification in Ring1-deficient forelimb buds accompany failures in repression of proximal signal circuitry bound by RING1B, including Meis2/1, and activation of distal signal circuitry in the prospective distal region. Additional deletion of Meis2 induced partial restoration of distal gene expression and limb formation seen in the Ring1-deficient mice, suggesting a critical role for RING1-dependent repression of Meis2 and likely Meis1 for distal specification. We suggest that the RING1/MEIS2/1 axis is regulated by early PD signals and contributes to initiation or maintenance of the distal signal circuitry.