Retinoic Acid and the Regulation of Amphibian Gliogenesis

The central nervous system includes both neurons and glial cells, which consist of astrocytes and oligodendrocytes. Glial cells are essential for the function and maintenance of the nervous system, and they play critical roles in tissue repair following neural injury. Surprisingly, how these cells originate during development has remained poorly understood. The proposed studies investigate the molecular signals required for the formation of glial cells during the development of the nervous system in the African Clawed Frog, which is an important animal model system for studies of embryonic development, cell biology, and neuroscience. Initial studies have delineated similarities and specific differences in glial development between frogs and mammals, and these differences may reflect new routes for the activation of genes required for glial development. These studies should reveal new mechanisms for the establishment and maintenance of glial cells. Since altered gene expression in glial cells can lead to forms of cancer or neurodegenerative diseases, the results of this work should expand the current view of how such alterations could arise in humans. They may therefore identify new opportunities for the development of therapies to reverse these altered patterns of gene expression and thus prevent the appearance or progression of disease. These studies will also provide a foundation for the development of instructional modules in science education through a collaboration with TeachHOUSTON, a University of Houston program that trains undergraduate STEM majors to become science teachers. The proposed work investigates transcriptional regulatory mechanisms underlying glial development in Xenopus laevis. The response of glial cells to injury and their roles in neural regeneration and repair suggest that glial lineages may have distinct developmental mechanisms to retain plasticity, and possibly even developmental potency, long after differentiation. Moreover, embryonic radial glial cells perform key glial functions (e.g., glutamate uptake) while retaining the capacity to initiate neurogenesis, a striking exception to the conventional view of cell fate specification. Preliminary results reveal divergence from the mammalian model of gliogenesis, anteroposterior regionalization of glial development, and a key role for retinoic acid, which mediates anteroposterior regionalization within the neural ectoderm. The proposed studies will examine specific roles for retinoic acid in the initiation of gliogenesis in the anterior spinal neurectoderm and the expansion of gliogenic gene expression throughout the embryonic brain and spinal cord. They will also identify genes and cis-regulatory regions associated with the emergence of glial lineages through a multi-modal analysis incorporating single-nucleus profiling of gene expression and chromatin accessibility. These results will advance current understanding of vertebrate glial development and the transcriptional regulatory networks underlying the emergence and maintenance of glial lineages. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.