Endocrine Abstracts

The primary cilium of cells detects and transduces extracellular signals, in particular, amplifying the SHH pathway, a key pathway required for pituitary development. FUZ is a planar cell polarity (PCP) effector, which is essential for normal ciliogenesis, required for recruiting retrograde intraflagellar transport proteins to the base of the organelle. The primary cilia of Fuz^-/- mutants are shorter or non-functional. Previous work has reported ciliopathy phenotypes in Fuz^-/- homozygous null mutants, including neural tube defects, craniofacial abnormalities and polydactyly, alongside PCP defects including kinked or curly tails and heart defects. Furthermore, in patients, FUZ variants are associated with a risk of neural tube defects and craniosynostosis. Interestingly, mouse mutants have no pituitary gland by 14.5dpc, but the cause of this phenotype has not been investigated. We analysed pituitary development in Fuz^-/- mouse mutants from the onset of Rathke’s pouch (RP) specification at 9.0dpc. Histological analyses reveal initial RP induction; however, RP fails to expand demonstrating elevated apoptosis and hypoplasia. Essential markers such as LHX3 and LHX4 are absent by 11.5dpc, indicating failure of anlage specification. Analyses of FGF, BMP and SHH signalling reveal reduced SHH pathway activation in the mutant, affecting anterior pituitary fate specification and normal development. Our findings suggests that primary cilia are required for normal pituitary development to mediate SHH pathway activity, and that mutations in FUZ may underly abnormal pituitary development and hypopituitarism.