NGF is produced by the tissues that these neurons innervate. When extra NGF is provided, extra sensory and sympathetic neurons survive, just as if extra target tissue were present. Conversely, in a mouse with a mutation that inactivates the gene for NGF or for its receptor (a receptor tyrosine kinase called TrkA), almost all sympathetic neurons and the NGF-dependent sensory neurons are lost. There are many neurotrophic factors, only a few of which belong to the neurotrophin family, and they act in different combinations to promote the survival and growth of different classes of neurons.
Formation of Synapses Depends on two-Way communication Between Neurons and their target cells
At journey’s end, the task of a growth cone is to halt its travels and make synapses with specific target cells. Synapses were introduced in Chapter 11, where we discussed channels and the electrical properties of membranes. Two main classes of synapses are found in vertebrates; those made with muscle cells and those made with other neurons. Synapse formation is best understood in the case of the highly specialized connections between motor neurons and skeletal muscle cells—so-called neuromuscular junctions (see Figure 11–38). During synapse formation, the axonal growth cone differentiates into a nerve terminal that contains synaptic vesicles filled with the neurotransmitter acetylcholine, while acetylcholine receptors become clustered in the muscle cell plasma membrane at the site of synapse formation. A synaptic cleft separates the preand postsynaptic plasma membranes, and a thin sheet of basal lamina lies in this space between them (Figure 21–82).
Figure 21–81 The survival of motor neurons depends on signals provided by the target muscles. (a) removal of the limb bud shortly after arrival of motor axons results in the death of motor neurons in the spinal cord on the amputated side.
(B) transplantation of an extra limb bud increases the survival of motor neurons. (after e. Kandel et al., principles of Neural Science, 5th ed., New York: McGraw hill Medical, 2012.)
Formation of the synapse involves two-way communication between the muscle cell and axonal growth cone: each of them, under the influence of the other, must reorganize the molecules on its side of the junction. The growth cone releases the signal protein Agrin, while the muscle expresses the Agrin receptor LRP4. Agrin binding to LRP4 stimulates association of LRP4 with MuSK, a receptor tyrosine kinase. LRP4 also serves as a signal in the reverse direction, from the muscle to the axon (Figure 21–83). During synapse formation, MuSK and LRP4 cluster in the muscle cell plasma membrane in the general neighborhood of the future synapse. As the growth cone approaches, it recognizes LRP4, which stimulates the differentiation of presynaptic structures in the nerve cell. At the same time, Agrin released from the growth cone binds to LRP4 in the muscle cell; this activates MuSK, and promotes a more focused clustering of acetylcholine receptors in the muscle cell membrane. Through these mechanisms, the reciprocal signaling of LRP4 from muscle to growth cone—and of Agrin from growth cone to muscle—induces the coordinated, localized differentiation of preand postsynaptic structures.
Synapse formation between neurons in the CNS is far more challenging, both for the neurons and for the scientists trying to understand the molecular basis of its specificity, and it remains poorly understood.