The Role of the Sonic Hedgehog Pathway in Normal Pituitary Development and Tumourigenesis

Mouse studies have demonstrated the necessity of sonic hedgehog (SHH) for normal proliferation of Rathke’s pouch (RP) precursors. However, the possible function of SHH in pituitary cell specification remains to be assessed. Additionally, evidence suggests that SHH may be relevant in human adamantinomatous craniopharyngioma (ACP), a benign, but aggressive childhood pituitary tumour associated with high morbidity. In this study I aim to determine the function of SHH during normal pituitary development and in human ACP. Specifically, I aim to test whether SHH is relevant for cell specification during pituitary development and whether it is pathogenic in ACP. In this study I show that conditional deletion of Shh in the Hesx1-cell lineage arrests RP development with complete loss of pituitary tissue by 12.5 dpc. Molecular analyses indicate that Shh is not only required for proliferation, but also, for normal specification of RP precursors. Without hypothalamic SHH signalling, critical RP progenitor markers are not expressed, leading to a change in cell fate. The results in this study also show that SHH is expressed in human ACP tumour samples, along with the direct targets, Gli1 and Ptch1, indicating pathway activation within these tumours. Conditional deletion of Shh in a murine ACP model revealed no difference in tumour formation/progression. However, SHH is still detected in non-targeted cells. Lastly, a pre-clinical trial using a small molecule inhibitor of the SHH pathway (Vismodegib, Roche) was performed. Results from the pre-clinical trial suggest that SHH may have a protective role in ACP pathogenesis. SHH pathway inhibition lead to a decrease in survival and an increase in the rate of tumourigenesis evidenced by an increase in proliferation and cells with clonogenic potential. In 4 conclusion, we reveal a novel role for SHH in the specification of RP precursors, demonstrate the activation of the pathway in human ACP and reveal the effects of SHH pathway inhibition on ACP tumourigenesis