ABSTRACT
The vertebral column or spine is the main structural element of the vertebrate body axis. It is assembled around
the notochord, a conserved axial structure that provides developmental cues for the development of other organs
and serves as a structural scaffold for the embryo in all chordates. Importantly, in vertebrates, the notochord also
attracts osteoblast precursors that give rise to the vertebral bodies of the spine. The vertebrate notochord is
composed of a core of highly conserved vacuolated cells that is surrounded by a thick extracellular matrix that
acts as a corset for the notochord rod. Importantly, loss of notochord vacuole function has been shown to cause
defects in vertebral formation and spine morphology that resemble congenital scoliosis (CS) in humans. While
genetic and embryological evidence clearly showed that the structural role of the notochord is conserved,
whether vacuolated cells function in vertebral patterning in mice as shown in zebrafish is not known. Moreover,
following vertebral patterning, notochord vacuolated cells form the nucleus pulposus (NP) at the center of the
intervertebral disc (IVD), where they remain until adulthood. However, little is known about the function of
vacuolated cells within the IVD. Also not known are the mechanisms that regulate notochord vacuole biogenesis
and integrity and how these are linked to IVD degeneration during aging. The proposed studies will investigate
mechanisms regulating notochord vacuole biogenesis and function in zebrafish and mice and will investigate the
role of notochord vacuoles in spine formation in mice. Altogether, these studies will bring important new insights
into spine morphogenesis and the origin of pathologies such as CS and disc disease.
