DESCRIPTION (provided by applicant): The coordination of spatial and temporal cues in the neural tube is essential for generating cell identity and diversity in the central nervous system (CNS). Here we test the role of the morphogen Sonic hedgehog (Shh) in coordinating these cues. In the vertebrate midline, secretion of Shh from the notochord is critical for inducing the floor plate in the overlying ventral neural tube, and subsequent production of Shh from this second signaling center. In a concentration and time dependent manner, Shh controls the identity and diversity of ventral neuronal subtypes along the dorsal-ventral (D/V) axis of the neural tube. Despite the large body of work that has established this mechanism, it is unknown how the hedgehog-patterning program is involved in generating cell identity and diversity along the anterior-posterior (A/P) axis. Using the developing hindbrain and the spinal cord as a model to represent the A/P axis, we explore this basic developmental question. We utilized genetic tools in the mouse to spatially and temporally dissect the function of the Shh pathway in both D/V and A/P axes. Our preliminary findings indicate that the hindbrain has a greater dependence and a longer requirement for floor plate-derived Shh compared to the spinal cord. This suggests that notochord-derived Shh plays a larger role in patterning the spinal cord than the hindbrain. Based on these findings, we test the hypothesis that spatial and temporal variations in the need for Shh result in the difference in cellular identity and diversity between the brain and the spinal cord. In aim 1 we will identify the combination of Shh transducers that mediate the difference in patterning between the hindbrain and the spinal cord. In aim 2 we ask how the early and late activities of hedgehog signaling in the notochord and the floor plate are coordinated to pattern the ventral neural tube. In aim 3 we will investigate how the Hox transcription factors, which provide positional information to progenitors along the A/P axis, and the Shh signaling pathway control cell diversity in the hindbrain from a common molecular ground state. Together, our studies will provide a conceptual framework for how different spatial and temporal cues are integrated at each level of the neural tube to generate the cellular profile that is unique for each division of the CNS.

The sonic hedgehog (Shh) morphogen is required for normal brain and spinal cord development. Here we test if the identity and diversity of cells from the brain to the spinal cord are determined by the production of Shh at different locations and times during embryogenesis. Determining the spatial and temporal contributions of Shh to neural development will provide insight into repairing and altering the course of genetic diseases of the central nervous system.