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NHMRC Early Career Fellowship (CJ Martin): Controlling the development and function of hindbrain commissures in vertebrate animals: the role of Robo3 receptor (2012–2016)

Abstract:
The hindbrain is an important component of the central nervous system in vertebrates that mediates many sensory and motor functions such as eye, facial and limb movement, proprioception, balance and respiration. To form the neuronal commissures that project between the two sides of the hindbrain and allow for bilateral function, guidance factors are present at the ventral midline and coordinate the growth and migration of the commissural neurons. One guidance factor that is emerging as a key regulator of hindbrain commissure formation is the Robo3 receptor, however, its function is not well understood and deficiency in Robo3 function can lead to severe neurological phenotypes such as oculomotor dysfunction and scoliosis. To determine the function of Robo3 during development of hindbrain commissures, this project will investigate three aims. First, identify binding partners that interact with Robo3 at the midline, including Netrin-1/DCC and Robo1/Robo2 which mediate chemoattractant and chemorepellent roles, respectively. Second, determine the role of Robo3 in guiding commissural axons and the mechanism underlying this process. Robo3 conditional knockout mice will be crossed with specific transgenic lines, to genetically manipulate subsets of commissural hindbrain projections, and the consequence of Robo3 deletion on axon guidance, migration and behaviour will be analysed. Third, determine how the genetic heterogeneity of Robo3 mutations can lead to a similar neurological phenotype. Site-directed mutagenesis will be used to reproduce similar Robo3 point mutations as found in patients with HGPPS (horizontal gaze palsy and progressive scoliosis), and the effect on Robo3 function and commissure formation will be analysed. The outcomes of this project will be important for the future study of oculomotor diseases and scoliosis, including the development of molecular therapies to ameliorate the effect of Robo3 deficiency.
Grant type:
NHMRC Training (Postdoctoral) Fellowship
Researchers:

  • Dr Peter Kozulin

    Postdoctoral Research Fellow
    School of Biomedical Sciences
    Faculty of Medicine
Funded by:
National Health and Medical Research Council