Charles H. Hood Foundation | David Breslow, Ph.D. – July 2018
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David Breslow -

David Breslow, Ph.D.

Assistant Professor of Molecular, Cellular & Developmental Biology

Yale University

Defining a Cilia-Lysosome Axis in Developmental Signaling and Cilium-Based Disease

 

Key Words: Primary Cilia, Ciliopathies, Signaling, Lysosome, Hedgehog Pathway, MTor Pathway, Intellectual Disability, Congenital Heart Defects, Medulloblastoma

The primary cilium is a protrusion from the cell surface that serves as a specialized center for signal transduction. A number of signaling pathways that control embryonic development, tissue homeostasis, and sensory signaling depend on cilia, and many signaling molecules localize to cilia during signaling. Consistent with key roles for cilia in signaling, ciliary defects promote tumorigenesis and also cause a group of inherited pediatric disorders known collectively as ciliopathies. Critically, while the importance of cilia is now recognized, the molecular mechanisms that support the assembly and function of cilia are not fully understood. Consequently, many ciliary disorders remain poorly characterized, and no effective treatments are available for children with ciliopathies.

 

Hedgehog pathway signaling is strictly dependent on primary cilia, and aberrant Hedgehog signaling contributes to congenital heart defects, brain malformations, and childhood medulloblastoma. To systematically investigate ciliary signaling, we recently conducted a genome-wide CRISPR-based screen using a Hedgehog pathway reporter. Strikingly, this unbiased screen identified many hit genes that act at lysosomes and late endosomes, suggesting that lysosomes are required for cilium function. Thus, our central hypothesis is that primary cilia depend upon lysosomes and that a cilia-lysosome axis plays key roles in ciliary signaling and ciliopathies. We will examine this hypothesis by 1) characterizing the lysosome-associated GTPases and their associated regulators and effectors, 2) dissecting the contribution of lysosomal nutrient sensing and intracellular positioning to specific aspects of cilium assembly and ciliary signaling, and 3) defining the role of the cilia-lysosome axis in stem cell fate determination and proliferation of medulloblastoma cells.

 

Together, these studies will provide new insights into how inter-organelle communication between cilia and lysosomes contributes to developmental signaling and childhood disease. We expect this work will also provide a foundation for future translational studies aimed understanding the cilia-lysosome axis in clinical and therapeutic contexts.