Despite recent advances in biomedical sciences, treatment options remain limited for patients suffering from stroke or other forms of brain injuries. Endogenous regenerative capacities in the brain hold therapeutic promise for nervous system repair after disease and injury. Throughout embryonic and postnatal development, neural progenitors/stem cells give rise to differentiated neurons, astrocytes, and oligodendrocytes. While these progenitors are relatively abundant during embryogenesis, they become restricted to specialized regions in the adult brain. In contrast to the well-investigated area of adult neural stem cell biology, relatively little is known about the cellular and molecular mechanisms controlling multiciliated ependymal cell (EC) function. As a primary cell type lining the adult brain ventricles, ECs form an important part of the lateral ventricular neurogenic niche, but their roles in postnatal/adult neurogenesis have long been controversial: whether ECs represent a neurogenic source remains unclear. Beyond ciliary movements, we know relatively little about basic ependymal biology. Using a combination of mouse genetics, biochemistry, and multiphoton live-imaging, we plan to elucidate the steps necessary to induce and control ependymal cellular plasticity. Our proposal is centered on basic molecular discoveries: we found that expression of the Foxj1 transcription factor, necessary for EC development from radial glial progenitors, is kept inherently unstable in mature ECs. Moreover, continued Foxj1 expression is required to prevent mature ECs from de-differentiating back into a progenitor-like state. We found that this surprising intrinsic cellular instability of mature ECs can be controlled by inhibitor of NF-?B kinase (IKK) signaling, a novel pathway distinct from cannonical NF-?B control. We plan to further explore these unexpected observations by determining the following: 1) whether the non- canonical IKK signal transduction pathway in ECs integrates extracellular signals to determine EC phenotypic stability; 2) what are the molecular mechanisms regulating Foxj1 transcription factor stability and proteolytic degradation - signaling cascades required to initiate EC de-differentiation; and 3) whether molecular events initiating de-differentiation of ECs represent the first steps toward their neurogenic transformation. Tackling the poorly-understood basic molecular and cellular mechanisms regulating EC biology, and using them as a basis for solving a long-standing problem on ependymal contributions to postnatal/adult neurogenesis, should further our understanding of CNS regenerative capacities in health and disease.
Our nervous system is critically important for learning, memory, and our perception of the world around us. Injuries to the nervous system are often debilitating, and difficult to treat since neurons do not regenerate themselves. This proposal examines the basic cellular biology of poorly understood multiciliated ependymal cells in the brain, and whether their unexpected properties can be utilized for regeneration.
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