Abstract
The primary cilium is a microtubule-based dynamic cellular appendage that is found in many cell types. Cilia
transduce cellular responses to extracellular signals, particularly to the morphogen hedgehog in vertebrates
during differentiation and proliferation, regulating morphogenesis in multiple tissues. However, the mechanisms
by which cilia-specific signals are maintained and propagated to direct downstream pathways during
morphogenesis is not well understood. Understanding signaling at cilia requires mechanistic understanding of
trafficking to cilia, isolating ciliary from extraciliary functions of signaling molecules, and studying functional
consequences directly in tissues without disrupting cilia. My group is one of the foremost in studying cilia-specific
signaling from subcellular to organismal scales, while preserving ciliary morphology. We identified the ciliary
trafficking adapter Tulp3 and key repressors of hedgehog pathway, Gpr161 and Ankmy2, both of which function
via cAMP signaling regulated by cilia. We postulate that the inherent complexity of ciliary signaling can be
understood by examining how signals are maintained in and propagated uniquely by cilia (compartmentalization)
and how cilia direct positive and negative regulation in downstream pathways (counterregulatory signaling). Over
the next five years, we will directly study how compartmentalization and counterregulatory signaling at cilia
regulates morphogenesis in different tissues. By leveraging our expertise in ciliary trafficking and hedgehog
pathway repression, and by using innovative mouse models, we will study the effect of ciliary signaling in the
following contexts. First, we will determine how counterregulatory signaling in cilia regulates renal tubular
homeostasis. We hypothesize that Tulp3 cargoes function as cystogenic ciliary signals that are normally inhibited
by polycystins. We propose to identify cystogenic drivers in cilia by identifying and perturbing cargoes of Tulp3
in preventing cysts. Second, we will determine the role of ciliary cAMP signaling in neural tube patterning and
closure. We hypothesize that hedgehog pathway repression by cAMP-protein kinase A signaling at cilia regulates
neural tube closure. We will determine role of adenylyl cyclase and protein kinase A compartmentalization in the
cilium-centrosomal complex in regulating hedgehog signaling strength, neural tube patterning, and closure.
Third, we will determine how cilia regulated repression of hedgehog pathway affects tissue morphogenesis. We
will test ciliary contributions to repression thresholds required for specific morpho-phenotypic outcomes by
perturbing ciliary compartmentalization of Gpr161 and adenylyl cyclases. Through this research we will identify
the features and consequences distinctive to signaling by cilia in directing tissue emergent properties. Our work
is cross-disciplinary and is supported by collaborators with expertise in proteomics, nephrology, neuropathology,
human genetics and embryology. Our research will expose new entry points for understanding complex
ciliopathy phenotypes and define translational opportunities for treating diseases caused by ciliary dysfunction.