THE ROLE OF NMYC AND CMYC IN SKIN DEVELOPMENT AND IN HEDGEHOG PATHWAY-INDUCED TUMORIGENESIS

RHONDA HUI PING KAN (2011). THE ROLE OF NMYC AND CMYC IN SKIN DEVELOPMENT AND IN HEDGEHOG PATHWAY-INDUCED TUMORIGENESIS PhD Thesis, Institute for Molecular Bioscience, The University of Queensland.

       
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Author RHONDA HUI PING KAN
Thesis Title THE ROLE OF NMYC AND CMYC IN SKIN DEVELOPMENT AND IN HEDGEHOG PATHWAY-INDUCED TUMORIGENESIS
School, Centre or Institute Institute for Molecular Bioscience
Institution The University of Queensland
Publication date 2011-08
Thesis type PhD Thesis
Supervisor Professor Brandon Wainwright
Total pages 239
Total colour pages 77
Total black and white pages 162
Language eng
Subjects 06 Biological Sciences
Abstract/Summary Members of the Myc family of proteins namely Nmyc, Cmyc and Lmyc are a group of basic helix-loop-helix transcription factors which have been implicated in the regulation of a plethora of cellular functions and whose dysregulated expression has been associated with a wide variety of human diseases. Given that the endogenous role of Myc family members in the skin has been poorly defined, particularly that of Nmyc, the role of Nmyc and Cmyc in postnatal skin development and homeostasis was first investigated. This was genetically tested via conditional deletion of Nmyc and/or Cmyc in the skin using the epithelial-specific K14Cre recombinase. While Nmyc and Cmyc expression levels were significantly reduced, Nmyc and/or Cmyc deficient mice exhibited normal postnatal skin histology with normal hair follicle (HF) cycling and did not result in transcriptional upregulation of other Myc family members. Hedgehog (Hh) signalling is required for proper embryonic development and postnatal homeostasis and its dysregulation is associated with a growing list of congenital disorders and human cancers including basal cell carcinoma (BCC). The majority of sporadic/familial forms of human BCCs have been linked to mutations in the HH signal receptor, PATCHED 1(PTCH1), which results in constitutive HH pathway activation. Nmyc has previously been shown to be ectopically expressed throughout BCC-like lesions that developed upon loss of Ptch1 activity in the skin. Further detailed investigation into Nmyc expression in Ptch1 deleted skin confirmed that Nmyc is upregulated specifically in late, but not initial, stages of BCC development. However, the functional significance of elevated Nmyc expression in Hh pathway-induced BCC is still unclear. Therefore, to examine the requirement for Nmyc and its cellular homologue Cmyc at different stages of BCC development, Nmyc and/or Cmyc were simultaneously deleted together with Ptch1 in the mouse skin using K14Cre. Deletion of Nmyc alone did not rescue the phenotypes of hyperproliferation, expansion of progenitor cell compartment and BCC-like lesion formation, which occur following loss of Ptch1 activity. Similarly, removal of Cmyc alone did not modify the early effects induced by loss of Ptch1. However, its function in the progression of BCC development could not be determined given these mice do not survive into adulthood. Transcriptional analyses in the skin of K14Cre;Nmyc;Ptch1 and K14Cre;Cmyc;Ptch1 mice identified increased expression of other Myc family members to compensate for their individual loss. Interestingly, although inactivation of both Nmyc and Cmyc did not attenuate the early Ptch1 deficient phenotype, their combined loss strongly suppresses the progression of BCC lesion formation namely by limiting the expansion and hyperproliferation of the epidermal progenitor cell compartment. In addition to the well-established cell autonomous role of mutation-driven activation of Hh pathway in cancers, there is accumulating evidence to support the importance of the stromal environment in supporting Hh pathway-induced tumour growth and progression. However, at the time when this project commenced, very little was known about the participation of the Hh pathway in regulating epithelial-mesenchymal interaction in BCC development. The paucity of knowledge about this interaction is mainly attributed to the fact that the analysis of such complex reciprocal interactions is difficult in vivo. Therefore, the aim of this part of the project was to establish an in vitro organotypic skin co-culture model which serves as a powerful tool to elucidate the role of Hh signalling in epithelial-mesenchymal interaction in the skin. Using a combined approach of an organotypic co-culture model and Ptch1 deleted cells, it was found that Hh pathway activation in either the epidermal or dermal compartment alone was unable to trigger the development of characteristic BCC-like lesions. Based on this observation, it was predicted that BCC development likely requires a complex reciprocal tumour-stroma interaction. In summary, this thesis demonstrates for the first time that although Nmyc and Cmyc are not functionally required in postnatal skin under homeostatic (physiological) conditions, overall Myc expression levels are critical determinants in driving progression, but not initiation, of Hh pathway-induced BCC tumour development.
Keyword Patched 1
Hedgehog Signalling
skin development and homeostasis
Mouse Model
Nmyc
Cmyc
basal cell carcinoma
tumour-stroma interaction
Microenvironment
Additional Notes 1,23,27,31,36,37,39,41,45,46,48,49,52,55,57,58,62,64,66,69,71,72,77,78,81,83,85,86,88,89,91,105,106,110-113,115,117,119,121,123,125-127,130,132,134,136,137,140,142,143,145,160,161,163,164,166,168,170,180,185,187-192,195,196,198-200,202,235,236

 
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Created: Wed, 08 Feb 2012, 19:28:53 EST by Ms Hui Kan on behalf of Library - Information Access Service