My graduate and postdoctoral training has impressed upon me the importance of understanding the molecular mechanisms of basic cell biological processes and their contribution to pathologies underlying human disease. As I prepare to transition into an independent research position, I'm compelled to acquire the additional technical skills and education that will enable me to gain research autonomy and develop an innovative basic research program addressing fundamental questions in cell and developmental biology. As a post-doctoral fellow with Elaine Fuchs at The Rockefeller University, I find myself in an ideal environment that will foster my continual growth as a scientist and mentor, and enable me to acquire additional technical expertise and generate research materials that will facilitate my future independent research endeavors. One fundamental question in developmental biology is how an individual cell may sense its environment to transmit extracellular signals that control cell signaling and proliferatin during tissue morphogenesis. This activation of developmental cell signaling pathways must be temporally and spatially regulated in order to balance tissue growth with differentiation. When this goes awry during normal tissue homeostasis, proliferative conditions such as polycystic kidney disease (PKD) and cancer arise. The long term objective of my proposal is to understand how primary cilia temporally and spatially regulate developmental signaling and cell proliferation during epidermal morphogenesis. The primary cilium is a microtubule-based cellular "antenna" that can sense the extracellular environment, transmit developmental signals, and influence cell-cycle progression. Dysfunctional cilia result in human genetic diseases referred to as "ciliopathies", and in diseases that precipitate the transition fro cellular quiescence to proliferation, such as PKD and cancer. Preliminary data indicate that primary cilia play at least two temporally and spatially distinct roles in balancing growth and differentiation during skin development: a novel, early role in epidermis, whose morphogenesis relies upon Notch signaling;and a later role in hair follicles, reliant upon Sonic Hedgehog (Shh) signaling. Although the reliance of Shh signaling on cilia is expected and well-characterized in other model systems, the molecular mechanisms underlying cilia-mediated control of Notch signaling and cell proliferation during epidermal morphogenesis are unknown. I hypothesize that spatial and temporal activation of Notch signaling and epidermal proliferation are directly regulated by primary cilia during normal skin development. To test this central hypothesis I will 1) Characterize the spatial and temporal localization and dynamics of notch signaling components at the primary cilia during cell division and differentiation. 2) Determine f known ciliary trafficking mechanisms regulate the localization, activation, and function of Notch signaling components during epidermal differentiation. 3) Identify the cell-cycle regulatory factors that function in cilia-mediated control of epidermal proliferation during skin differentiaton and hair follicle morphogenesis.
The primary cilium is a cellular antenna that can sense the extracellular environment, transmit developmental signals, and influence cell-cycle progression. Non-functional cilia contribute to proliferative diseases such as polycystic kidney disease and cancer, and cause a spectrum of genetic diseases called ciliopathies, which affect numerous organ systems and tissues. The diversity of organ systems affected in these human genetic diseases highlight the necessity to develop tissue-specific model systems, such as the skin, to study the function of primary cilia during differentiation, tissue morphogenesis, cell proliferatio and cancer.
|Ezratty, Ellen J; Pasolli, H Amalia; Fuchs, Elaine (2016) A Presenilin-2-ARF4 trafficking axis modulates Notch signaling during epidermal differentiation. J Cell Biol 214:89-101|