Education:
BA 1990 Natural Sciences - Cambridge University
MSc 1992 Biology - Princeton University
PhD 1997 Molecular Biology - Princeton University
Postdoctoral Research Fellowship:
1997-2003 Columbia University
Started at USC: 2003
Research Topics: Developmental Biology, Human/Mammalian Genetics, Neurogenetics, Cellular Neurobiology
Research Description
A fundamental problem in neurobiology is to understand the mechanisms that establish connections between neurons. During development, neurons extend axons along complex pathways towards their synaptic targets, resulting in the precisely ordered networks that underpin the diverse functions of the nervous system. Growth cones, at the tips of axons, translate guidance cues in the extracellular environment into a stereotyped binary response: movement towards or away from a particular signal. The identification of individual guidance cues is a critical step towards understanding both the mechanisms by which axons navigate and the signal transduction machinery that results in cytoskeletal rearrangements in the growth cone. We are studying a class of spinal sensory axons in the developing mammalian spinal cord, for which this problem is tractable.
Commissural neurons differentiate bilaterally, adjacent to the dorsal midline of the developing spinal cord, and project dorso-ventrally around the circumference of the spinal cord. After crossing the floor plate, commissural axons turn to project rostrally,towards the brain. Commissural growth cones use several guidance cues during this trajectory. A diffusible chemorepellent activity secreted by the roof plate provides the earliest guidance cue for commissural axons, directing them away from the dorsal midline as they begin their ventral trajectory. The roof plate chemorepellent is mediated by two members of the BMP (Bone Morphogenetic Protein)subfamily of TGF-beta signaling molecules present in the roof plate, BMP7 and Growth and Differentiation Factor (GDF) 7, acting together as a BMP7:GDF7 heterodimer. Growth towards the floor plate is mediated by Netrin-1, a diffusible chemoattractant secreted by floor plate cells. On reaching the floor plate, commissural growth cones are also guided by cues in the extracellular matrix of the neuroepithelium and on the surface of floor plate cells. After crossing the floor plate, commissural axons become refractory to Netrin-1 signaling.
The identification of the roof plate chemorepellent demonstrated a novel role for the BMP family of signalling molecules, distinct from its roles in tissue patterning and cell type specification. Commissural neurons depend on BMPs several times during their development: BMPs act first to induce neural identity, and then serve as axon guidance cues. An intriguing possibility raised by this work is that molecules initially used to induce the formation of distinct neuronal subtypes may be reused as guidance cues. The finding that the guidance activity of BMPs lies in the formation of heterodimers suggests a way in which this diversity of BMP function can be achieved and opens up new possibilities for studying the mechanisms that tranduce BMP signals. The identification of the roof plate chemorepellent, together with the identification of the floor plate chemoattractant, also provides an opportunity to examine the mechanisms through which sequential diffusible signals are integrated by the growth cone, thus controlling the axonal trajectory of a single class of neuron.
Selected Publications
Yamauchi K, Phan KD, Butler SJ. - BMP type I receptor complexes have distinct activities mediating cell fate and axon guidance decisions. - Development [ 2008 ] Feb 13; . PubMed
Butler SJ, Tear G. - Getting axons onto the right path: the role of transcription factors in axon guidance. - Development [ 2007 ] Feb;134(3):439-48 . PubMed
