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Altered neural cell fates and medulloblastoma in mouse patched mutants
L V Goodrich1, L Milenković, K M Higgins
1Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305-5427, USA.
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.
Insights
The PATCHED (PTC) gene is crucial for development, acting as a Sonic hedgehog (Shh) receptor. Its inactivation causes developmental defects, highlighting its role in regulating Shh target genes and preventing diseases like basal cell nevus syndrome.
Area of Science:
- Developmental biology
- Genetics
- Molecular biology
Background:
- The PATCHED (PTC) gene encodes a receptor for Sonic hedgehog (Shh) and functions as a tumor suppressor.
- Defects in the PTC gene are associated with basal cell nevus syndrome (BCNS).
Purpose of the Study:
- To investigate the functions of the PTC gene by creating and analyzing mouse models with inactivated PTC.
- To understand the role of Ptc in the regulation of Shh signaling pathways during embryonic development.
Main Methods:
- Gene inactivation in mice to create homozygous and heterozygous ptc mutant models.
- Analysis of embryonic development, neural tube morphology, and gene expression patterns (ptc and Gli).
Main Results:
- Homozygous ptc mutant mice exhibited embryonic lethality with severe neural tube defects (open and overgrown).
- Shh target genes (ptc and Gli) were derepressed in specific embryonic tissues, and their expression patterns were aberrantly altered in the neural tube.
- Heterozygous ptc mutant mice showed increased size and developed abnormalities mirroring human BCNS, including hindlimb defects and cerebellar medulloblastomas.
Conclusions:
- Ptc is essential for repressing genes activated by Shh, playing a critical role in embryonic development.
- The study validates the Ptc gene's function as a tumor suppressor and its involvement in BCNS pathogenesis.
- Mouse models provide valuable insights into the molecular mechanisms underlying Shh pathway regulation and associated developmental disorders.