regulating motor neuron survival is completed, trophic signals continue to be required to promote cell growth and to sustain target innervation.

1.3. Signal transduction from neurotrophins and neurotrophin receptors

The interactions of members of neurotrophin family, including NGF, brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3, NT-4/5, and NT-6/7 with their receptors, TrkA, TrkB, TrkC, and p75NTR (p75 neurotrophin receptor), play important roles in the development of the nervous system and the maintenance and repair of adult nervous system. The outcome of such neurotrophin-mediated interactions is dependent on the cell type and the expression pattern of each neurotrophin receptor. The activation of tropomyosin receptor kinase (Trk) receptors induces survival and differentiation of neurons. The activation of p75NTR in the absence of a strong Trk signal induces apoptosis of neurons, whereas in the presence of Trk signaling, p75NTR acts a coreceptor to enhance response to neurotrophins. Although the role of targets in controlling neuronal cell death historically has received the most attention, signals derived from afferent inputs and nonneuronal cells such as central and peripheral glia and endocrine glands are also possible sources of trophic regulation of cell death and survival.

1.3.1. Signals for survival

Trk receptors belong to the receptor tyrosine kinase family that regulates synaptic strength and plasticity in the mammalian nervous system. The three most common types of Trk receptors are TrkA, TrkB, and TrkC. Each of these receptors types has different binding affinity to certain types of neurotrophins, which are trophic factors mediating neuronal survival. Each neurotrophin family member is synthesized as an approximately 250–amino acid precursor (proneurotrophin) that is processed into a roughly 120–amino acid mature neurotrophins by furins and prohormone convertases. Secreted neurotrophins form homodimer and activate Trk receptors by promoting receptor dimerization. On binding of NGF, Trk receptors autophosphorylate in the cytoplasmic tail, which forms the docking sites for downstream signaling molecules such as phospholipase Cγ, phosphoinositide 3-kinase (PI3K), and adaptor proteins such as Shc (Figure 11-2). The activation of PI3K and mitogen-activated protein (MAP) kinases play important roles in regulating neuronal survival.

Figure 11-2. Trk and p75NTR signaling pathways. Neurotrophins bind Trk receptors or p75NTR to activate survival or apoptotic signaling pathways. On ligand binding, activated Trk receptors dimerize and autophosphorylate the cytoplasmic domains, which provides docking sites for three principal downstream signaling pathways, phospholipase C pathway, Ras-MAP kinase pathway, and PI3K-Akt pathway. These pathways lead to nuclear translocation of transcription factors, such as CREB and NFκB, and ultimately regulation of gene expression. Phosphorylation of the members of Forkhead family inhibits their translocation into the nuclei, which reduces the expression of Forkhead target genes that promote apoptosis. The binding of neurotrophins or proneurotrophins to p75NTR can activate Bad via JNK cascade and eventually leads to the release of e ectors from mitochondria and caspase activation. There are cross-talks between the survival and proapoptotic signaling cascades.

The role of the PI3K pathway in neuronal survival was initially suggested by the observation that PI3K inhibitors block the ability of NGF to prevent apoptosis in a neuron-like cell line, PC12 cells. Activation of PI3K leads to the production of the various 3-phosphorylated phosphoinositide lipid signaling molecules, among which either phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) or phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) binds and regulates the serine/threonine protein kinase Akt. Later studies on SCG neurons showed that either PI3K activation or constitutively active Akt expression keeps sympathetic neurons alive in the absence of NGF. Activated Akt mediates the phosphorylation of proapoptotic protein Bad and caspase-9, which contributes to the inhibition of apoptosis. Activated Akt also promotes cell survival by regulating at least three transcription factor families: Forkhead, cAMP-response element-binding protein (CREB), and nuclear factor kappa B (NF-κB). Phosphorylation of the members of Forkhead family inhibits their translocation into the nuclei, which reduces the expression of Forkhead target genes that promote apoptosis, such as the Fas ligand. Phosphorylation of CREB and IκB kinase (IKK) stimulates the transcription of prosurvival genes by CREB and NF-κB.

Activated Trk receptors provide the docking site for Shc, which triggers the activation of the Ras-Raf-MAP