RUI: Hedgehog dependent cranial neural crest cells pattern the zebrafish forebrain.

Smith College, Northampton MA

Investigators

Abstract

The most frontal portion of the vertebrate brain known as the forebrain controls many essential bodily functions, including our executive abilities. Deciphering the cellular and molecular mechanisms underlying the construction of the forebrain is central to our understanding the development of the central nervous system (CNS) and how the vertebrate brain has evolved. Zebrafish represent a tractable animal to study brain development. Hundreds of externally developing zebrafish embryos are easily obtained, the essential stages of embryonic brain development are completed over 1-2 days, and many genetic techniques are available that enable highly sophisticated microscopy to monitor live zebrafish brains developing over time. This proposal uses the zebrafish to determine whether a transient population of migrating stem cells, known as “neural crest cells,” directly influences the birth of neurons and establishment of neural connections in the early embryonic forebrain. Neural crest cells are well-known to migrate away from the early forming CNS and contribute to a diversity of tissues, but they are not known to contribute directly to the CNS. This proposal challenges this notation and plans to innovatively employ light-sheet microscopy to record the migratory behaviors of neural crest cells to and within the zebrafish forebrain during commissure formation. Such findings would be paradigm shifting and have a significant impact on our understanding of brain development. The broader impacts activities include fostering collaborations between two different scientific disciplines (developmental and computational biology), new course development, and engaging the public in science communication through a new traveling art show. The importance of neural crest cells to building the peripheral nervous system, supporting glandular and pigment development, and sculpting the craniofacial skeleton among other roles cannot be understated. Despite this long history of studying the role of neural crest in the development of tissues outside the central nervous system (CNS), their function on the development of the brain itself has been largely overlooked. This proposal hypothesizes that cranial neural crest cells (CNCCs) navigate to and pattern commissure formation and neurogenesis in the zebrafish forebrain. The proposal takes advantage of the zebrafish model system to track CNCC migration to the forebrain and test their requirement for forebrain patterning and commissure formation. It will use complementary fate mapping approaches to determine if CNCCs do in fact migrate with pathfinding commissural axons and enter the telencephalon where they directly contribute to neurogenesis. Such findings would be both significant and novel as this would be the first demonstration that CNCCs directly influence axon pathfinding in the CNS, and that they may migrate back into the brain to directly support CNS neurogenesis. The proposal will also interrogate the role radial glia play in restricting most CNCCs from entering the brain. A mechanism of migrating CNCCs transiently influencing the brain in diverse ways would have significant broader impacts on our understanding of CNS development. Additional broader impact activities include development of a neurodevelopment course-based undergraduate research experience (CURE) course, fostering collaborations with computational and data scientists, and a traveling art show to engage the public. 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.