Biological Sciences

Martyn D. Goulding Associate Professor, The Salk Institute e-mail: goulding@salk.edu

     We are studying the signals that regulate the development of different cell types in the vertebrate spinal cord and mesoderm that lie adjacent to the spinal cord. In particular, we are interested in the role transcription factors play in controlling cell identity and cell behaviours such as axon pathfinding and migration. 

SPINAL CORD
     The adult spinal cord plays a central role in integrating sensory information and controls muscle movements via the regulated firing of motor neurons. The activity of motor neurons is controlled by multiple interneurons cell types that are distributed throughout the gray matter of the spinal cord. Previous studies have shown that the position that a cell occupies along the dorsoventral axis of the embryonic spinal cord is a major determinant of its identity. We have characterized three dorsoventrally restricted populations of interneurons in the ventral spinal cord that are defined by expression of the transcription factors EVX1, EN1 and CHX10. All three cell types appear to be components of reflex pathways in the spinal cord that control posture and locomotion. We are currently using a variety of genetic and molecular approaches in mice to study these three cell types. These include gene knockouts and genetically marking different neuronal cell types with axonal tracers such as tau-lacZ. Using these approaches, we have shown that each of these interneuron populations has a characteristic axon morphology, enabling us to begin dissecting the genetic pathways that generate these different axon morphologies. 

     Our studies on the EN1 expressing interneurons show they are a population of local projecting interneurons that have motor neurons as their target and mice lacking the En1 gene exhibit axon pathfinding defects in these neurons. We are currently investigating other genes that control axon pathfinding and synapse formation by these cells. In addition, we are testing a number of transcription factors for their ability to change the fate of the EN1+ neurons. Our overall goal is to understand how each of these different interneuron cell types contributes to the physiology of reflex pathways in the adult. 

MUSCLE DEVELOPMENT
     Our studies on the development of skeletal muscles have focused on the role of the transcription factor PAX3 in these events. We have shown that PAX3 controls the migration of hypaxial (limb, diaphragm and tongue) muscle precursors and that this regulation involves changes in the expression of the receptor tyrosine kinase c-met. We are currently determining if c-met is a downstream target of PAX3 in vivo and delineating the regulatory sequences that control c-met expression in migrating muscle precursors. We are also examining the role played by a second transcription factor, LBX1, that is specifically expressed in muscle precursors that undergo long range cell migration in the embryo. 

      Maroto, M., Reshef, R., Munsterberg, A. Koester, S., Goulding, M. and Lassar, A.B. (1997) Ectopic Pax-3 activates MyoD and Myf-5 expression in both embryonic mesoderm and in neural tissue. Cell 89: 139-148. 

      Burrill, J., Moran, L., Goulding, M. and Saueressig, H. (1997) Pax2 is expressed in multiple spinal cord interneurons, including a population of En1+ interneurons that require Pax6 for their correct specification. Development 124: 4493-4503. 

      Daston, G., Lamar, E., Olivier, M. and Goulding, M. (1996) Pax-3 is necessary for migration but not differentiation of limb muscle precursors in the mouse. Development 122: 1017-1027. 

      Bang, A.G. and Goulding, M. (1996) Regulation of vertebrate neural cell fate by transcription factors. Curr. Opin. Neuro. 6: 10-17.