Figure 21–71 Programmed production of different types of neurons at different times from dividing progenitors in the cerebral cortex of the brain of a mammal. close to one face of the cortical neuroepithelium, progenitor cells divide, in stem-cell fashion, to produce successive generations of neurons (colored here blue, green, red, orange, and black). the neurons migrate out toward the opposite face of the epithelium by crawling along the surfaces of radial glial cells, as shown in Figure 21–70. the first-born neurons settle closest to their birthplace, while neurons born later crawl past them to settle farther out. Successive generations of neurons thus occupy different layers in the cortex and have different intrinsic characters according to their birth dates.
contacts an unfavorable surface, it withdraws; when it contacts a more favorable surface, it persists longer, steering the growth cone in that direction. In this way, the growth cone is guided by subtle variations in the properties of the surfaces over which it moves. At the same time, it is sensitive to specific signaling molecules, which—as we discuss next—can either encourage or hinder its advance.
a Variety of extracellular cues Guide axons to their targets
Growth cones generally travel toward their targets along predictable routes, according to programs stored in the memory of the particular neuron to which they belong (Movie 21.7). In the simplest case, a growth cone can take a route that has been pioneered by other neurites, which they follow by contact guidance. As a result, nerve fibers in a mature animal are usually found grouped together in tight parallel bundles (called fascicles or fiber tracts). Such crawling of growth cones along axons is partly mediated by homophilic cell–cell adhesion molecules— membrane glycoproteins that help a cell displaying them to stick to any other cell that displays the same molecules. As discussed in Chapter 19, many homophilic adhesion molecules fall into one of two main classes: they are members of either the immunoglobulin superfamily, such as N-CAM, or the Ca2+-dependent cadherin family, such as N-cadherin. Members of both families are generally present on the surfaces of growth cones, of axons, and of various other cell types that growth cones crawl over, including glial cells in the central nervous system and muscle cells in the periphery of the body. Growth cones also migrate over components of the extracellular matrix. When tested with neurons growing in a culture dish, some of the matrix molecules, such as laminin, favor axon outgrowth, while others, such as chondroitin sulfate proteoglycans, discourage it. But exactly how the matrix functions to guide axons in intact animals remains to be discovered.
Growth cones are generally guided by a succession of different cues at different stages of their journey, as summarized in Figure 21–73. Many of these cues involve specific signaling molecules. Some of these are encountered in the extracellular matrix, while others are attached to the plasma membrane of cells that the growth cones touch. Another important part is played by chemotactic factors; these are proteins secreted from cells that act as beacons at strategic points along the path—some attracting, others repelling. The trajectory of commissural axons— axons that cross from one side of the body to the other—provides a well-studied example.
Commissural axons are a general feature of bilaterally symmetrical animals, such as us, because they are required to coordinate behavior of the two sides of the body. In the developing spinal cord of a vertebrate, for example, a large number of neurons send their axonal growth cones ventrally toward the floor plate (the same structure that we encountered earlier as a source of the morphogen Sonic hedgehog—see Figure 21–69). The growth cones cross the floor plate and then turn abruptly through a right angle to follow a longitudinal path up toward the brain, parallel to the floor plate but never again crossing it (Figure 21–74). The first stage of the journey depends on a concentration gradient of the signal protein Netrin, secreted by the cells of the floor plate: the commissural growth cones sniff their way toward its source.