Suppressors of hedgehog signaling: Linking aberrant development of neural progenitors and tumorigenesis.

Subversion of signals that physiologically suppress Hedgehog pathway results in aberrant neural progenitor development and medulloblastoma, a malignancy of the cerebellum. The Hedgehog antagonist RENKCTD11 maps to chromosome 17p13.2 and is involved in the withdrawal of the Hedgehog signaling at the granule cell progenitor transition from the outer to the inner external germinal layers, thus promoting growth arrest and differentiation. Deletion of chromosome 17p, the most frequent genetic lesion observed in this tumor, is responsible for the loss of function of RENKCTD11, resulting in upregulated Hedgehog signaling and medulloblastoma. Persistence of signals that limit Hedgehog activity is also associated with malignancy. Hedgehog signaling- induced downregulation of ErbB4 receptor expression is attenuated in medulloblastoma subsets in which the extent of Hedgehog pathway activity is limited, thus favoring the accumulation of ErbB4 with imbalanced alternative splice CYT-1 isoform over the CYT-2. This is responsible for both Neuregulin ligand-induced CYT-1-dependent prosurvival activity and loss of CYT-2-mediated growth arrest.