Altered Neural Cell Fates and Medulloblastoma in Mouse patched Mutants

Abstract

The PATCHED (PTC) gene encodes a Sonic hedgehog (Shh) receptor and a tumor suppressor protein that is defective in basal cell nevus syndrome (BCNS). Functions of PTC were investigated by inactivating the mouse gene. Mice homozygous for the ptc mutation died during embryogenesis and were found to have open and overgrown neural tubes. Two Shh target genes, ptc itself and Gli, were derepressed in the ectoderm and mesoderm but not in the endoderm. Shh targets that are, under normal conditions, transcribed ventrally were aberrantly expressed in dorsal and lateral neural tube cells. Thus Ptc appears to be essential for repression of genes that are locally activated by Shh. Mice heterozygous for the ptc mutation were larger than normal, and a subset of them developed hindlimb defects or cerebellar medulloblastomas, abnormalities also seen in BCNS patients.

Hedgehog signaling promotes the degradation of tumor suppressor Sufu through the ubiquitin–proteasome pathway

“…Again, the rapid turnover of Sufu observed above was blocked by MG132 (Figure 2b), suggesting that activation of Shh signaling causes Sufu to be degraded in the proteasomes. To further investigate the physiological relevance of the observed regulation of Sufu protein turnover, we isolated torsos of E9.5 embryos with Ptch1 À/ þ or Ptch1 À/À genotypes (Goodrich et al, 1997), and quantified the levels of Sufu by western analysis. Because Ptch1 is a potent inhibitor of Smo, Sufu protein is thus expected to be unstable in the Ptch1 null embryos in which the Shh pathway is constitutively active (Goodrich et al, 1997).…”

“…To further investigate the physiological relevance of the observed regulation of Sufu protein turnover, we isolated torsos of E9.5 embryos with Ptch1 À/ þ or Ptch1 À/À genotypes (Goodrich et al, 1997), and quantified the levels of Sufu by western analysis. Because Ptch1 is a potent inhibitor of Smo, Sufu protein is thus expected to be unstable in the Ptch1 null embryos in which the Shh pathway is constitutively active (Goodrich et al, 1997). Indeed, our results showed a dramatic reduction of Sufu protein level in the homozygous Ptch1 À/À embryos compared with that in the heterozygous littermates ( Figure 2d).…”

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Su(Fu) null mouse mutants not only fail to repress the pathway (Svard et al, 2006), but have some phenotypes similar to inactivation of Ptch1. Although Ptch1 þ /À mice are predisposed to developing medulloblastoma and rhabdomyosarcoma, and basal cell carcinomas following irradiation (Goodrich et al, 1997;Hahn et al, 1998;Aszterbaum et al, 1999b), Su(fu) þ /À mice mainly develop a skin phenotype characterized by basaloid epidermal proliferations. Moreover, Su(Fu) null MEFs and wild-type cells treated with Su(Fu) siRNAs display Hh pathway activation, supporting a central role in pathway repression (Svard et al, 2006).…”

Turning heads: Development of vertebrate branchiomotor neurons

“…Hh binding to Ptc relieves inhibition of Smo, resulting in the activation of Gli transcription factors and Hh-responsive gene expression. In Ptc knockout mouse embryos, the neural tube is ventralized due to ectopic activation of Smo function (and Hh signaling), likely resulting in the induction of ectopic motor neurons at all axial levels (Goodrich et al, 1997). Conversely, expression of a Ptc deletion variant that inhibits Smo function irrespective of the presence of Hh ligand leads to dorsalization of the neural tube and to the cell-autonomous repression of motor neuron induction in chick embryos .…”