The complex pattern of gene activity is clearly evident in forelimb level motor neurons in the chick spinal cord, which express PEA3 (red) and Isl1 (blue). At this level, pectoralis motor neurons can be identified by injecting the tracer chemical HRP into the pectoralis muscle. Cell bodies of pectoralis motor neurons contain HRP (green) and also express PEA3 and Isl1.
Photo: Thomas M. Jessell/HHMI at Columbia University

Back to the Beginning

Jessell’s research on the development of the vertebrate CNS began with an interest in neuropharmacology. While pursuing undergraduate studies at the University of London, Jessell became curious about the events involved in chemical transmission in the CNS. That interest then led to graduate work at Cambridge University, where he studied how the spinal cord integrates sensory information from the periphery.

He soon realized, however, that the neural circuitry underlying this process was dauntingly complex. "I thought it rather intimidating to try to understand the circuitry of the CNS in its mature state," Jessell says. "So I decided that one way to learn about the principles that control the organization of neural circuits might be to try to understand how such circuits are assembled during development."

While the developmental chronology of the CNS is fairly well cataloged, the genetic and biochemical processes that construct neural circuits cell by cell—as fast as 250,000 cells per minute—are only now coming to light. These processes, collectively called programs of cellular differentiation, occur during early development and provide the paths by which undefined cells are converted into highly specialized ones.

A passage from the textbook, Principles of Neural Science, which is edited by Jessell and fellow HHMI investigator Eric R. Kandel and James H. Schwartz, both at Columbia University, traces the modern concept of differentiation to the work of Jacques Monod and Francois Jacob: "Monod and Jacob proposed that cell differentiation is achieved by the activation of specific sets of genes, with each distinct cell type expressing a different subset of genes. The differential activation of specific genes within individual cells is now known to be controlled, in a direct manner, by nuclear proteins that bind to DNA sequences, thereby regulating the transcription of specific genes."

A cell also differentiates itself from surrounding cells in part by "sensing" and responding to chemical cues in its environment or to physical contact with other cells. Each of these cues pushes a cell farther along its destined path of differentiation—and closer to determining its final fate. Eventually what was once an undifferentiated neural progenitor cell becomes, for example, a motor neuron that controls the movement of a specific muscle, or a sensory neuron that relays information into the spinal cord from the skin, limbs and muscles.

Differentiation occurs on a grand scale in the CNS, where overall "the number of different neuronal cell types is thought to exceed 100, far more than any other organ in the body," says Jessell." In the CNS, the entire process of differentiation can be reduced to five basic steps: First, a set of cells in the embryo’s outermost layer is specified to become neural progenitor cells. Second, these cells then separate into broad populations of immature neurons and supporting structures called glial cells. Third, the immature neurons migrate to their final positions. Fourth, they send axons, the leading edge of a developing neuron, through the surrounding tissues, to seek their proper targets. Finally, in the spinal cord, for example, specific motor and sensory neurons form the connections, or synapses, that complete the circuit between muscle and nerve.

In humans this sequence of events begins during the third week of gestation. At that time, a long, thin sheet of cells deep within the early embryo curls upon itself to form the neural tube, a structure that ultimately provides the scaffold out of which the brain and spinal cord finally emerge.

In vertebrates, muscle-specific motor neurons are grouped into families called motor pools. These neurons deliver the commands from the CNS that coordinate movement. Sensory, or afferent, neurons, which pair with motor neurons to form complete circuits, provide status reports back to the spinal cord from the joints and muscles. 

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