Uncovering mechanisms controlling notochord vacuole and spine morphogenesis

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Abstract In vertebrates the notochord plays critical signaling roles during vertebrate development and acts as a hydrostatic skeleton for the embryo before bone formation. At the center of the vertebrate notochord is a large fluid-filled organelle, the notochord vacuole. These fluid-filled vacuoles have been described in every vertebrate embryo studied including fish, amphibians, birds, and mammals. In these species the vacuoles persist within the nucleus pulposus of the intervertebral discs (IVD's), well beyond skeletal maturity, where they remain osmotically active and continue to play signaling roles. Surprisingly, little was known about the molecular mechanisms involved in notochord vacuole biogenesis and maintenance. Recent work in zebrafish from our laboratory has shown that notochord vacuoles are specialized lysosome-related organelles. We established that notochord vacuoles are required for antero-posterior (AP) axis elongation during embryonic development and identified a novel role for this fluid filled organelle in spine morphogenesis. We found that loss of vacuole integrity leads to kinks in the spine axis similar to those observed in congenital scoliosis (CS) patients. Thus, the vertebrate notochord plays a critical role in spine morphogenesis. Our goal here is to use the zebrafish system to uncover molecular mechanisms controlling notochord vacuole formation and maintenance and to characterize the role these vacuoles play in spine morphogenesis. These studies will help better understand the etiology of congenital scoliosis and other poorly understood spine defects as well as IVD processes associated with aging.