Roberts syndrome (RBS) is a rare genetic disorder characterized by craniofacial abnormalities, limb malformation, and often severe mental retardation. RBS arises from mutations in ESCO2 that encodes an acetyltransferase that modifies the cohesin subunit SMC3. Cohesins are critical for both inter-molecular DNA-DNA tethering (such as between sister chromatids) and intra-molecular DNA tetherings (stabilizing the base of DNA loops). It remains unclear which activity is adversely affected, although current models suggest that RBS arise through mitotic failure and limited progenitor cell proliferation due to premature sister chromatid separation. However our findings using the zebrafish regenerating fin reveal that Esco2 depletion results in significant defects in both tissue regeneration and bone segment growth in the absence of elevated levels of apoptosis. In pursuing evidence obtained from genomic studies in mice and zebrafish, we found that Esco2 is a critical regulator of cx43/gja1 (encodes the gap junction connexin subunit required for cell–cell communication) expression. The link between Esco2 and Cx43 is of immense interest since cx43 mutations cause oculodentodigital dysplasia (ODDD) in humans and the skeletal defects of the mutant short fin (sofb123). ODDD patients exhibit developmental defects that overlap with those of both RBS and a related disorder CdLS, conceptually linking ODDD to cohesinopathies. Among additional evidence that Esco2 and Cx43 function in a common pathway, we demonstrated that miR-133-dependent cx43 overexpression rescues esco2-dependent growth defects. Further, preliminary evidence suggests that the target of Esco2-dependent acetylation, Smc3, is similarly critical for cx43 expression. These results provide strong evidence that ESCO2 plays a transcriptional role critical for human development and that RBS arises through dysregulation of developmental programs.