In vivo enhanced expression of patched dampens the sonic hedgehog pathway.
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.
Bergstein
Ivan
I
Division of Pulmonary and Critical Care Medicine, Weill Medical College of Cornell University, New York, New York, 10021, USA.
Leopold
Philip L
PL
Sato
Noboru
N
Panteleyev
Andrei
A
Christiano
Angela
A
Crystal
Ronald
R
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015870:Gene Expression; D015316:Genetic Therapy; D018859:Hair Follicle / Q000254:growth & development; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008543:Melanins / Q000096:biosynthesis; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010641:Phenotype; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics*
D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008543:Melanins; D008565:Membrane Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D015534:Trans-Activators