Grant: Project Grant

Some very severe human developmental disorders are caused by dysfunction of the microscopic hair-like structure (primary cilium). Primary cilium projects from most cells in the human body and acts like a "GPS- antenna" to survey the environment outside cells and transduce this information into inside the cell so that the cells can adjust their shape, movement and proliferation and other functions during organ development. It is therefore not surprising that defects in primary cilia lead to a wide-range of congenital abnormalities affecting brain, heart, skeleton, and kidneys. Ciliopathies are incurable and may cause fetal death, considerable morbidity after birth or reduced longevity. Investigation of the functions of the genes mutated in humans is crucial if we want to find a cure for ciliopathies. We focus on a specific group of genes (Fuzzy, Inturned and Wdpcp), termed PCP effectors. Mutations in these 3 genes are associated with various human ciliopathies which feature facial and rib defects, neural tube defects, and cystic kidneys. Mouse mutants for these genes have severe malformations which resemble features of humans with PCP effector gene mutations. Using cells and mice bearing mutations of the Fuzzy as our main experimental model, we will try to identify and explain the mechanisms through which loss of Fuzzy (and its molecular partners, Inturned and Wdpcp) disturbs generation of cilia and distorts the cilial signals that are so crucial for normal development. Based on our studies, we hope to offer novel therapeutic strategy for the severe human developmental defects caused by the mutation in the PCP effector genes and, likely, other ciliopathies.