Epidermal hyperplasia and expansion of the interfollicular stem cell compartment in mutant mice with a C-terminal truncation of Patched1.
Hedgehog (Hh) signaling is conserved from flies to humans and is indispensable in embryogenesis and adulthood. Patched (Ptc) encodes a receptor for Hh ligands and functions as a tumor suppressor. PTCH1 mutations in humans are found in basal cell carcinoma (BCC) and irradiated Ptc1(+/-) mice recapitulate this phenotype. However, due to embryonic lethality associated with the Ptc1 null mutation, its normal function in embryonic and adult skin remains unknown. Here we describe the epidermal phenotypes of a spontaneous and viable allele of Ptc1, Ptc1(mes), in which the C-terminal domain (CTD) is truncated. Ptc1(mes/mes) embryos display normal epidermal and hair follicle development. Postnatal Ptc1(mes/mes) skin displays severe basal cell layer hyperplasia and increased proliferation, while stratification of the suprabasal layers is mostly normal. Interestingly, truncation of the Ptc1 CTD did not result in skin tumors. However, long term labeling studies revealed a greater than three-fold increase in label-retaining cells in the interfollicular epidermis of Ptc1(mes/mes) adults, indicating possible expansion of the epidermal stem cell compartment. Increased expression of regulators of epidermal homeostasis, c-Myc and p63, was also observed in Ptc1(mes/mes) adult skin. These results suggest that the CTD of Ptc1 is involved in regulating epidermal homeostasis in mature skin.
Nieuwenhuis
Erica
E
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, University of Toronto, Toronto Medical Discovery Towers, 101 College Street, Toronto, Ontario, Canada M5G1L7.
Barnfield
Paul C
PC
Makino
Shigeru
S
Hui
Chi-Chung
CC
D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D017931:DNA Primers / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D016259:Genes, myc; D053823:Hedgehog Proteins / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D006965:Hyperplasia; D017403:In Situ Hybridization; D051379:Mice; D008817:Mice, Mutant Strains; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D017384:Sequence Deletion; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D012868:Skin Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*
D017931:DNA Primers; D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse