Patched 1 and patched 2 redundancy has a key role in regulating epidermal differentiation.
The Patched 1 (Ptch1) receptor has a pivotal role in inhibiting the activity of the Hedgehog (Hh) pathway and is therefore critical in preventing the onset of many human developmental disorders and tumor formation. However, the functional role of the mammalian Ptch2 paralogue remains elusive, particularly the extent to which it contributes to regulating the spatial and temporal activity of Hh signaling. Here we demonstrate in three independent mouse models of epidermal development that in vivo ablation of both Ptch receptors results in a more severe phenotype than loss of Ptch1 alone. Our studies indicate that concomitant loss of Ptch1 and Ptch2 activity inhibits epidermal lineage specification and differentiation. These results reveal that repression of Hh signaling through a dynamic Ptch regulatory network is a crucial event in lineage fate determination in the skin. In general, our findings implicate Ptch receptor redundancy as a key issue in elucidating the cellular origin of Hh-induced tumors.
Division of Molecular Genetics and Development, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
Christelle
C
Adolphe
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Erica
E
Nieuwenhuis
Division of Molecular Genetics and Development, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
Rehan
R
Villani
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Zhu Juan
ZJ
Li
Epithelial Stem Cell Biology Laboratory, Research Division, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
Pritinder
P
Kaur
Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. Electronic address: cchui@sickkids.ca.
Chi-Chung
CC
Hui
Division of Molecular Genetics and Development, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. Electronic address: b.wainwright@imb.uq.edu.au.
Brandon J
BJ
Wainwright
D000818:Animals; D021461:Animals, Outbred Strains; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage / Q000502:physiology; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology / Q000378:metabolism; D005260:Female; D018859:Hair Follicle / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D016513:Mice, SCID; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D000072082:Patched-2 Receptor; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016038:Skin Transplantation
D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; C000606238:PTCH2 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D000072082:Patched-2 Receptor; C000606240:Ptch1 protein, mouse; C000606241:Ptch2 protein, mouse; D011956:Receptors, Cell Surface