Vertebrate neurons use a similar self-avoidance strategy to pattern their axons and dendrites, but instead of DSCAMs, they use protocadherins for self/non-self discrimination. The Protocadherin locus encodes 58 related cadherin-like trans-membrane proteins that are expressed in different combinations in single neurons. Homophilic recognition results in self-avoidance of dendrites emanating from the same neuron; neighboring dendrites of different neurons express different protocadherins and thus evade repulsion. Thus, although insect DSCAM and vertebrate protocadherin proteins share no sequence homology, they mediate similar self-avoidance strategies.
Eventually, axonal growth cones reach the target region where they must halt and make synapses. These synapses, as a rule, are destined to transmit neural signals in one direction, from axon to target cell. The development of synapses, however, depends on signaling in both directions: signals from the target tissue not only help control which growth cones synapse where (as we discuss shortly), but can also regulate how many of the innervating neurons survive.
Many types of vertebrate neurons are produced in excess; up to 50% or more of some of them die soon after they reach their target, even though they appear perfectly normal and healthy up to the time of their death. About half of all the motor neurons that send axons to skeletal muscle, for example, die within a few days after making contact with their target muscle cells. A similar proportion of the sensory neurons that innervate the skin die after their growth cones have arrived there.
This large-scale normal neuronal death often seems to reflect the outcome of a competition, in which the target tissue releases a limited amount of a specific neurotrophic factor that the neurons innervating the tissue require to survive; those that do not get enough die by programmed cell death. If the amount of target tissue is increased—for example, by grafting an extra limb bud onto the side of the embryo—more limb-innervating neurons survive; conversely, if the limb bud is cut off, the same neurons all die (Figure 21–81). In this way, although individuals may vary in their bodily proportions, they always retain the right number of motor neurons to innervate all their muscles and the right number of sensory neurons to innervate their body surface. The strategy of overproduction followed by death of surplus cells may seem wasteful, but it provides a simple and effective means to adjust the number of innervating neurons according to the amount of tissue requiring innervation.
The first neurotrophic factor to be identified, and still the best characterized, is called nerve growth factor (NGF )—the founding member of the neurotrophin family of signal proteins. It promotes the survival and growth of specific classes of sensory neurons and of sympathetic neurons (a subclass of peripheral neurons that control contractions of smooth muscle and secretion from exocrine glands).
Figure 21–80 DSCAM mediates self-avoidance of dendrites. (a) Sensory neurons in the Drosophila peripheral nervous system extend dendrites along the larval body wall. the image shows the dendrites of a regular array of photosensing neurons (red), which allow the larva to detect and avoid harmful light. the posterior epidermal cells of each segment are labeled in blue. there are many neurons, and those shown here spread out their dendrites into overlapping fields.
(B) Mutations at the Dscam locus upset the way the various dendrites interact, changing the rules of self-avoidance and the distribution of innervation. (a, courtesy of chun han; B, after D. hattori et al., Annu. Rev. Cell Dev. Biol. 24:597–620, 2008. With permission from annual reviews.) 2.5 day chick section of spinal cord 9 day chick (A) section of spinal cord