The primary Cilia are cell surface organelles essential for vertebrate embryonic development and physiological activities of adult organs. Multiple human diseases, including Polycystic Kidney Diseases (PKD), Bardet-Biedl Syndrome (BBS) and Meckel-Gruber Syndrome (MKS), are associated with the dysfunction of cilia. The long-term goals of our lab is to reach a comprehensive understanding of the mechanisms underlying the regulation of cilia biogenesis, as well as the roles for the cilia in cell-cell communication, cell polarity control as well as the development of a variety of organs. Our current research focuses on the following topics

1. The relationship between cilia and signal transduction. We have shown that cilia play a significant role in regulating the intracellular signal transduction of the Hedgehog (Hh) pathway in mammals. Multiple components of the Hh pathway, including Patched-1, Smoothened, Gli2, Gli3 and Suppressor of fused (Sufu), are localized to the cilia. However, the importance of such localization remains unclear. We focus on the relationship between cilia and two of the Hh pathway components, Sufu and Gli. Sufu is an important negative regulator of Hh signaling in both fruit flies and mammals, and its activity seems to be regulated in response to Hh signaling. In collaboration with Dr. Rune Toftgard in Karolinska institute, we are addressing the roles for cilia in the regulation of Sufu and Gli activities through genetics and molecular biology approaches. We are also searching for proteins directly responsible for Gli transport in the cilia.

2. The roles for PCP effector genes in cilia biogenesis and cell polarity control. Taking a forward genetic approach, we generated Double-thumb (Dtm), a recessive mouse mutant with both morphological and behavioral defects. We discovered that these defects result from a missense mutation in Inturned (Intu), a gene involved in cell polarity control in the fruit flies. We have generated several tissue-specific mutants for this gene through an embryonic stem (ES) cell-based approach, and discovered that Intu is an essential regulator of cilia biogenesis in mammals. We are currently addressing the roles for this gene in both embryonic development and disease pathogenesis, such as PKD.

3. Hearty (Hty), a novel regulator of cilia biogenesis. We identified Hty through the study of another recessive mouse mutant generated in our forward genetic screen. Hty mutants exhibit multiple defects in embryonic development as the result of a partial loss of cilia. The Hty protein is a novel vertebrate-specific protein specifically localized to the primary cilia. We are currently investigating the molecular mechanism underlying the Hty function through multiple approaches.