Adp

TrkA

TrkB

Tyrosine kinase

TrkC

▲ FIGURE 22-28 Specificity of neurotrophins for Trks, a family of receptor tyrosine kinases. Each neurotrophin binds with high affinity to one Trk receptor indicated by the solid arrow from the ligand to the receptor. NT-3 also can bind with lower affinity to both TrkA and TrkB as indicated by the dashed arrow. In addition, neurotrophins bind to a distinct receptor called p75NTR either alone or in combination with Trks. NGF = nerve growth factor; BDNF = brain-derived neurotrophic factor; NT-3 = neurotrophin-3. [Adapted from W. D. Snider, 1994, Cell 77:627.]

Neurotrophin Receptors Neurotrophins bind to and activate a family of receptor tyrosine kinases called Trks (pronounced "tracks"). (The general structure of receptor tyrosine kinases and the intracellular signaling pathways they activate are covered in Chapter 14.) As shown in Figure 22-28, NGF binds to TrkA; BDNF, to TrkB; and NT-3, to TrkC. Binding of these factors to their receptors provides a survival signal for different classes of neurons. A second type of receptor called p75NTR (NTR = neurotrophin receptor) also binds to neurotrophins, but with lower affinity. However, p75NTR forms heteromulti-meric complexes with the different Trk receptors; this association increases the affinity of Trks for their ligands. Some studies indicate that the binding of NGF to p75NTR in the absence of TrkA may promote cell death rather than prevent it.

Knockouts of Neurotrophins and Their Receptors To critically address the role of the neurotrophins in development, scientists produced mice with knockout mutations in each of the neurotrophins and their receptors. These studies revealed that different neurotrophins and their corresponding receptors are required for the survival of different classes of sensory neurons, which carry signals from peripheral sensory systems to the brain (Figure 22-29). For instance, pain-sensitive (nociceptive) neurons, which express TrkA, are selectively lost from the dorsal root ganglion of knockout mice lacking NGF or TrkA, whereas TrkB- and TrkC-expressing neurons are unaffected in such knockouts. In contrast, TrkC-expressing proprioceptive neurons, which detect the position of the limbs, are missing from the dorsal root ganglion in TrkC and NT-3 mutants.

Wild Type

Spinal Mechanoreceptors

Spinal Mechanoreceptors

Muscle Motoneurons

Mutant Mutant

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