Increasing Sufu gene dosage reveals its unorthodoxical role in promoting polydactyly and medulloblastoma tumorigenesis

Suppressor of Fused (SUFU) is widely regarded as a key negative regulator of the Sonic Hedgehog (SHH) morphogenic pathway and a known tumor suppressor of medulloblastoma (MB). However, we report here that SUFU expression was markedly increased in 75% of specimens compiled in a tissue array comprising 49 unstratified MBs. The SUFU and GLI1 expression levels in this MB array showed strong positive correlation, which was also identified in a large public dataset containing 736 MBs. We further report that increasing Sufu gene dosage in mice caused pre-axial polydactyly, which was associated with the expansion of the Gli3 domain in the anterior limb bud and heightened Shh signaling responses during embryonic development. Increasing Sufu gene dosage also led to accelerated cerebellar development and, when combined with ablation of the Shh receptor encoded by Patched1 (Ptch1), promoted medulloblastoma tumorigenesis. These data reveal multi-faceted roles of SUFU in promoting MB tumorigenesis by enhancing SHH signaling. This revelation clarifies potentially counter-intuitive clinical observation of high SUFU expression in MBs and may pave way for novel strategies to reduce or reverse MB progression.