Abstract – The Role of Patched1 in Epidermal Homeostasis Hedgehog (Hh) signalling is a critical pathway involved in the development of many, if not all, organ systems. However the abnormal activation of Hh signalling in fully developed adult organs leads to cancer. Mutation of the Hh signal receptor, Patched1 (Ptc1), causes Naevoid Basal Cell Carcinoma Syndrome, which presents with developmental defects and cancer predisposition. The activation of Hh signalling is seen in a wide range of non-inherited cancer types also, including Medulloblastoma and Basal Cell Carcinoma (BCC) of the skin. BCC is the most common form of human cancer and over 90% of cases are linked to abnormally high Hh signalling. Hh signalling is known to regulate hair follicle morphogenesis during development and more recently has been linked to modulation of the embryonic epidermal stem cell compartment. However both the mechanisms behind this process and the mechanism behind its induction of BCC are still uncharacterised. The aim of this project was to determine the role of Ptc1 in the skin, particularly the adult stem cell compartment, and the role of Hh signalling in BCC formation. The deletion of Ptc1 specifically in the adult epidermis was enabled by the creation of a K14-Cre Recombinase induced Ptc1 Conditional (K14-Cre:Ptc1C/C) transgenic mouse line. Proliferation was increased throughout the epithelia and BCC-like lesions developed within 4 weeks of Ptc1 deletion. This indicates that Hh signalling plays a critical role in repressing cell turnover in the interfollicular epithelium (IFE) and bulge region in the adult despite being previously reported not to play a role in this area. Ptc1 deletion in the epithelia was also found to promote the IFE lineage over hair follicles and expand the expression of many proposed stem cell markers, including K15, Sox9 and p63. K14-Cre:Ptc1C/C transgenic mice also exhibited a severe growth defect, linked to low levels of Igf1 hormone in the serum. Igf1 binding protein alteration in the skin was determined to be the most likely cause and prompted the investigation of Igf axis signalling in Ptc1 deleted epidermis. Insulin-like growth factor binding protein 2 was found to localise to the bulge or stem cell region of the hair follicle, and was increased in K14-Cre:Ptc1C/C epidermis. Igfbp2 was coincident with a loss of PI3K/Akt signal translation. The majority of human BCC samples also expressed Igfbp2 at much higher levels than surrounding normal tissue indicating these results are relevant to the human BCC condition also. Interestingly Hh activation was also shown to increase p38 MAPK throughout the epidermis indicating it is a universal target of Hh signalling in the skin. In summary we have found that Hh signal activation in the epidermis promotes the bulge/stem cell and interfollicular lineages of the skin at the expense of hair follicles. Finally the modulation of PI3K/Akt signalling by Igfbp2 in the bulge is perhaps mediating the effect of Hh signalling via the promotion of the bulge lineage leading to the development of BCC.
| Identifer | oai:union.ndltd.org:ADTP/254061 |
| Creators | Rehan Villani |
| Source Sets | Australiasian Digital Theses Program |
| Detected Language | English |
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