Staining shows which proteins are present during different stages of motor neuron development. Hindlimb level motor neurons in the chick spinal cord express the ETS protein PEA3 (red) and the LIM homeodomain protein Isl1 (blue). External femorotibialis motor neurons labeled in green express neither PEA3 nor Isl1.
Photo: Thomas M. Jessell/HHMI at Columbia University
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Sketching Early Events
After more than a decade of research, Jessell and his colleagues together with HHMI investigator David J. Anderson at the California Institute of Technology believe their teams have sketched out some of the critical molecular events that must occur to form one part of the circuit between nerve and muscle cells.
Most early signals for motor neuron differentiation come from the nearby mesodermal tissues that adjoin the neural tube. The notochord, a primitive structure that vanishes as the embryo grows, plays a key role in orchestrating embryonic development. However, HHMI researchers have unexpectedly found one instance where the final defining signal for differentiation of motor and sensory neurons does not come from a nearby source.
Jessell, Anderson, and their colleagues have found that the motor and sensory neurons that constitute a single nerve circuit both express transcription factors of the ETS gene family. Furthermore, the researchers found that ETS genes define which clusters of developing motor neurons will connect to specific embryonic muscles and receive inputs from defined sets of sensory neurons. Their work was published in the October 30, 1998, issue of the journal Cell.
The researchers found that sensory neurons, the return wires that relay information about what muscles are doing back to the CNS, express the same ETS proteins as their matching target motor neurons. This result was unexpected, says Jessell, because sensory neurons develop essentially independently from motor neurons—yet, ultimately, the ETS proteins are found to match within a completed circuit.
"One way to achieve that match could be to provide a coordinating signal from the peripheral target of both sets of neurons—the limb," explains Jessell. In other words, the target itself might play a role in constructing the proper connections within the spinal cord.
Indeed, Jessell, Anderson and their colleagues demonstrated this by removing limb buds from chick embryos. (Limb buds are small regions of tissue that eventually form wings and legs.) If the scientists removed a limb bud before ETS gene expression begins, they found that the motor and sensory neurons lacked their final ETS identities. As soon as ETS proteins appeared, however, neither motor nor sensory neurons needed their target to continue developing properly.
The results of these studies, which were performed with investigators in the laboratories of Cynthia Lance-Jones at the University of Pittsburgh School of Medicine and Tetsuichiro Saito at Japan’s National Institute of Genetics, indicate the power of molecular approaches in defining the forces that drive nervous system development.
