Current Research and Scholarly Interests
Early embryonic development is governed by an exquisite interplay of genes that organizes cells as they proliferate. Signals flow between cells to control their fates; information inherited by the cells influences their responses to the signals. Transcription factors necessary for forming particular parts of the bodysuch as head-to-tail differences, heart, eyes, or nervous systemhave remained dedicated to those tasks through evolution. Similarly, the genes and proteins that code for signals, signal receptors, and information transfer within the cell have been preserved. We study evolutionarily conserved regulators in flies and in mice to learn how the embryo is constructed and how pattern-organizing genetic programs arose, function, and change. Genetic damage to developmental regulators can lead to cancer, birth defects, and neurodegeneration; we study all of these processes in the context of the development of the mammalian cerebellum.
The Hedgehog Signaling System in Development and Cancer
The evolutionarily conserved Hedgehog (Hh) signaling system is used in most animals to control the embryonic development of numerous tissues, such as brain and spinal cord, limbs, skeleton, and skin. We study how the Hh protein signal is received, transduced, and interpreted, using mice and flies. We study how Hh signaling controls cell differentiation and patterning in structures as diverse as the fly wing and the developing mammalian cerebellum. Mutations in human PATCHED (PTCH), which encodes the Hh receptor, cause birth defects and medulloblastoma of the cerebellum, the most common childhood malignant brain tumor. PTCH mutations caused by UV lead to basal cell carcinoma of the skin, the most common human cancer. We are using mutant ptc mouse models to investigate how normal cerebellum cells become tumor cells. Using high-throughput sequencing and chromatin analyses, we have identified batteries of genes that are directly regulated by Hh signals in normal and cancerous cells. We are studying mechanisms of selective target gene control, and how the targets contribute to normal development or cancer. We are studying detailed mechanisms of Hh signal transduction, particularly the roles of primary cilia, remarkable organelles where Hh signals are transduced. We have identified new components of Hh signaling and are investigating their roles. In collaboration with Professor Josh Elias, we are using mass spectrometry to characterize early events in responses to Hh signaling. In collaboration with Professor W.E. Moerner, we are analyzing the movements of single protein molecules during Hh transduction. In collaboration with researchers at BGI and with Professor Serafim Batzoglou we are analyzing genome alterations that occur during the growth of mouse and human cancers, employing single-cell exome sequencing.
Biology of the Niemann-Pick type C syndrome, a neurodegenerative and lysosome storage disorder
Children mutant in either of the two NPC genes undergo neurodegeneration and usually die by the teenage years. Mutant cells accumulate masses of sterols in aberrant organelles due to defective intracellular trafficking. In humans and mice, NPC disease causes the death of the Purkinje neurons of the cerebellum and damage to other tissues. We have engineered mice in which labeled, functional NPC proteins can be provided to specific cell types in otherwise mutant mice, thus allowing analyses of cell type-specific components of the overall pathology, and analyses of the movements and functions of NPC proteins within cells. We have created two different models of the disease in Drosophila in order to apply genetics to identifying and analyzing interacting genes. Our goals are to learn the mechanisms of NPC protein actions, and to learn how NPC proteins preserve functions and survival of specific cell types. We are using Drosophila genetics to identify interacting genes that may affect NPC protein functions.