Samantha J. Butler

Assistant Professor, Neurobiology

Research Topics

1. Characterization of the signaling pathway(s) that mediates the diverse activities of the BMPs
2. Integration of sequential guidance cues by growth cones
3. Use of embryonic stem cells to re-establish dorsal neurons in the spinal cord

Research Overview

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. My work seeks to understand the molecular mechanisms used by a novel class of axon guidance cues, the Bone Morphogenetic Proteins (BMPs), to polarize commissural neurons, a class of spinal interneurons.

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. Commissural axons use at least two diffusible guidance cues during this trajectory. The roof plate provides the earliest guidance cue for commissural axons secreting a diffusible chemorepellent, which directs axons away from the dorsal midline. This chemorepellent is mediated by two members of the BMP family 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.

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.