Related Experiment Videos
In vivo enhanced expression of patched dampens the sonic hedgehog pathway
Ivan Bergstein1, Philip L Leopold, Noboru Sato
1Division of Pulmonary and Critical Care Medicine, Weill Medical College of Cornell University, New York, New York, 10021, USA.
Abstract:
The sonic hedgehog (SHH)-patched (PTCH) pathway functions in normal embryonic development of the brain, musculoskeletal system, and hair follicles, and in normal post-natal control of hair follicles. Dysregulation of the pathway has been implicated in a variety of neoplasias, including those of skin and brain. Based on the knowledge that generalized, prolonged PTCH expression can inhibit the effects of SHH signaling, we tested the hypothesis that localized transient overexpression of PTCH would inhibit the phenotype of SHH-induced accelerated growth of hair follicles. Adenovirus (Ad)-mediated transient over-expression of Shh (AdShh) in telogen (8 weeks) mouse skin induced anagen hair growth as demonstrated by histology and gross appearance. Strikingly, local intradermal administration of a Ptch-expressing adenovirus (AdPtch), but not a Null control adenovirus (AdNull), 18 hours before AdShh injection, significantly blocked this phenotype, with 100% of AdPtch+AdShh mice failing to advance to anagen compared with AdNull+AdShh mice and AdShh mice (30% and 45% failing to advance to anagen, respectively). Thus, PTCH expression mediated by gene transfer can modulate the SHH signaling pathway in the adult mammal and may serve as a starting point for therapies relevant to clinical conditions resulting from dysregulation of this pathway as well as for strategies to suppress normal SHH-dependent processes, such as hair growth.
Insights
Localized transient overexpression of Patched (PTCH) using gene transfer can inhibit Sonic Hedgehog (SHH) signaling. This finding offers potential therapeutic strategies for SHH pathway dysregulation and hair growth control.
Area of Science:
- Molecular Biology
- Developmental Biology
- Dermatology
Background:
- The Sonic Hedgehog (SHH)-Patched (PTCH) pathway is crucial for embryonic development and hair follicle regulation.
- Pathway dysregulation is linked to various cancers, including skin and brain neoplasms.
- Understanding SHH pathway modulation is key for therapeutic interventions.
Purpose of the Study:
- To investigate if localized, transient PTCH overexpression can inhibit SHH-induced hair follicle growth.
- To explore the potential of gene transfer for modulating SHH signaling in adult mammals.
Main Methods:
- Adenovirus-mediated gene transfer was used to overexpress Shh (AdShh) and Ptch (AdPtch) in mouse skin.
- AdPtch was administered 18 hours prior to AdShh injection in telogen phase mouse skin.
- Histology and gross appearance were used to assess hair growth (anagen induction).
Main Results:
- AdShh injection induced anagen hair growth in mouse skin.
- Pre-treatment with AdPtch completely blocked AdShh-induced anagen (100% failure to advance).
- Control groups (AdNull+AdShh, AdShh alone) showed partial or no blockage of anagen induction.
Conclusions:
- PTCH expression via gene transfer effectively modulates the SHH signaling pathway in adult mammals.
- This approach could form the basis for therapies targeting SHH pathway dysregulation.
- Gene transfer of PTCH may offer strategies to suppress SHH-dependent processes like hair growth.