Research

Martyn D. Goulding, a professor in the Molecular Neurobiology Laboratory, studies the early development of the nervous system. He focuses on how interneurons, responsible for communication between nerve cells in the spinal cord, and motor neurons, which cause muscles to contract, are generated in the embryonic spinal cord. Knowing more about how these cells form will further understanding of how to regenerate and reconnect the many types of nerve cells that are necessary for moving our muscles.

His lab studies a family of genes known as the Pax genes. They have discovered that one of its members, Pax-3, determines which cells will become part of the spinal cord. A significant indication of the gene's importance has been the identification of Pax-3 mutations in a human disorder called Waardenburg Syndrome. Further knowledge of how Pax-3 functions should provide important insights into other birth defects, including exencephaly and spina bifida.

"We are focusing our efforts on how different types of spinal cord 'interneurons'—neurons that bridge communications between sensory and motor neurons—control how we move and how we respond to touch and pain. Knowing more about how these cells develop and function is a critical step in devising new therapies to regenerate and activate circuits in the spinal cord following injury."

Once a toddler has mastered the art of walking, it seems to come naturally for the rest of her life, but walking and running require the coordinated activity of at least 200 muscles. The choreographer is a specialized network of interneurons in the spinal cord–commonly referred to as CPG, short for central pattern generator–that functions as a local control and command center for the rhythmic movements that underlie locomotion.

Although scientists had known about the locomotor CPG for a long time, they were unable to identify the nerve cells that make up these circuits. When Goulding's lab and others began to break the molecular code that makes these different interneuron cell types, they could start to unravel the wiring of the spinal cord to see how it works. Previously, Goulding and his team discovered that a subset of inhibitory interneurons, the V1 neurons, control the speed of motor rhythm and thus set the pace at which animals walk, while a second group of inhibitory neurons, called V0 neurons, govern the left-right alternating pattern of activity that is needed for stepping, as opposed to hopping, movements.

In their latest study, they set their eyes on a group of elusive neurons whose job it is to ensure that flexors and extensors don't get in each other's way: When you flex your arm, the biceps need to contract, while the triceps need to relax, and vice versa when you extend your arm. Their experiments revealed that the reciprocal pattern of flexor and extensor muscle activity is generated by the composite action of the V1 neurons and a second class of inhibitory neurons of a different embryonic origin. Strikingly, they found that the same neurons are present in the cords of swimming vertebrates, leading Goulding to propose that the "walking" CPG is an evolutionary adaption of the "swimming" CPG circuit.

The findings mark an important milestone in understanding the neural circuitry that coordinates walking movements, one of the main obstacles in developing new treatments for spinal cord injuries.

Left to right:
Back row: Jingming Zhang, Floor Stam, Olivier Britz, Tim Hendricks

Front row: Aurore Giraudin, Chris Padilla, Lidia Garcia-Campmany, Martyn Goulding, Becky Hensley, Ying Zhang, Marta Garcia del Barrio, Tommie Velasquez

Selected Publications

Gross, M.K., Moran-Rivard, L., Velasquez, T., Nakatsu, M.N., Jagla, K., and Goulding, M.D. (2000). Lbx1 is required for muscle precursor migration along a lateral pathway into the limb. Development 127, 413-424.

Moran-Rivard, L., Kagawa, T., Saueressig, H., Gross, M.K., Burrill, J., and Goulding, M.D. (2001). Evx1 is a postmitotic determinant of V0 interneuron identity in the spinal cord. Neuron 29, 385-399.

Dottori, M., Gross, M.K., Labosky, P., and Goulding, M.D. (2001). The winged-helix transcription factor Foxd3 suppresses interneuron differentiation and promotes neural crest cell fate. Development 128, 4127-4138.

Gross, M.K., Dottori, M., and Goulding, M.D. (2002). Lbx1 specifies somatosensory association interneurons in the dorsal spinal cord. Neuron 34, 535-549.

Sapir, T., Geiman, E.J., Wang, Z., Velasquez, T., Mitsui, S., Yoshihara, Y., Frank, E., Alvarez, F.J., and Goulding, M. (2004). Pax6 and Engrailed 1 regulate two distinct aspects of Renshaw cell development. J. Neurosci. 24, 1255-1264.

Cheng, L., Arata, A., Mizuguchi, R., Qian, Y., Karunaratne, A., Gray, P.A., Arata, S., Shirasawa, S., Bouchard, M., Luo, P., Chen, C.L., Busslinger, M., Goulding, M., Onimaru, H., and Ma, Q. (2004). Tlx3 and Tlx1 are post-mitotic selector genes determining glutamatergic over GABAergic cell fates. Nat. Neurosci. 7, 510-517.

Lanuza, G.M., Gosgnach, S., Pierani, A., Jessell, T.M., and Goulding, M. (2004). Genetic identification of spinal interneurons that coordinate left-right locomotor activity necessary for walking movements. Neuron 42, 375-386.

Goulding, M., and Pfaff, S.L. (2005). Development of circuits that generate simple rhythmic behaviors in vertebrates. Curr. Opin. Neurobiol. 15, 14-20.

Kriks, S., Lanuza, G.M., Mizuguchi, R., Nakafuku, M., Goulding, M. (2005). Gsh2 is required for the repression of Ngn1 and specification of dorsal interneuron fate in the spinal cord. Development 132, 2991-3002.

Gosgnach, S., Lanuza, G.M., Butt, S.J., Saueressig, H., Zhang, Y., Velasquez, T., Riethmacher, D., Callaway, E.M., Kiehn, O., Goulding, M. (2006). V1 spinal neurons regulate the speed of vertebrate locomotor outputs. Nature 440, 215-219.

Mizuguchi, R., Kriks, S., Cordes, R., Gossler, A., Ma, Q., and Goulding, M. (2006). Ascl1 and Gsh1/2 control inhibitory and excitatory cell fate in spinal sensory interneurons. Nat. Neurosci. 9, 770-778.

Zhang, Y., Narayan, S., Geiman, E., Lanuza, G.M., Velasquez, T., Shanks, B., Akay, T., Dyck, J., Pearson, K., Gosgnach, S., Fan, C.M., and Goulding, M. (2008). V3 spinal neurons establish a robust and balanced locomotor rhythm during walking. Neuron 60, 84-96.

Salk News Releases

• Prestigious endowed chairs awarded to Salk scientists
  March 30, 2012
• A fine balance
  October 8, 2008
• Salk neurobiologist receives Javits Neuroscience Investigator Award
  June 15, 2006
• Striking the right balance between excitation and inhibition
  May 31, 2006
• Salk researchers make fast strides towards understanding how our body controls walking
  March 14, 2006

Awards and Honors

• Pew Scholar, 1994-1998
• Basil O'Connor Research Award, 1993-1995
• Jacob Javits Neuroscience Investigator Award, 2006

Links

Goulding lab