Neurotrophins in Neural Crest Development

Neurogenesis in the sympathetic ganglia is governed by precursor proliferation, followed by a period of apoptosis as neuroblasts that fail to innervate their target tissues die, while others complete functional maturation. Upon innervation of their target tissues, neuroblast survival is mediated by growth/survival factors called neurotrophins (NTs). Neurotrophins exist as precursor proteins (proNTs) that are processed to mature NT proteins. The NT family of secreted growth factors include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3, and NT-4/5 that bind to their cognate tyrosine kinase receptors TrkA, TrkB, and TrkC (Fig. 15.1). Neurotrophins bind and facilitate dimerization of Trk receptors, activating their intrinsic tyrosine kinase activities that initiate a kinase cascade that transmits signals to the nucleus to regulate genes important in neural survival and growth (Teng and Hempstead 2004). Both proNTs and mature NTs bind to the p75 receptor, which has limited homology to death receptor transmembrane proteins (Fig. 15.1). Recent evidence indicates that proNT interacts solely with p75 and in association with an accessory re-ceptor,sortilin,is a potent death signal (Nykjaer et al.

Figure 15.1

The cognate receptors for neurotrophins (NGF, BDNF, NT-3, and NT4/5). The p75 or nerve growth factor receptor (NGFR) binds all pre-processed (i.e., pro-NGF) and processed neurotrophins with equal affinity. p75 shares homology with the death receptor family of signaling receptors and this receptor may transmit either death-inducing or survival signals depending on cell type and context. Different neurotrophins interact selectively with distinct members of the Trk family of tyrosine kinase receptors. The structure of the Trk receptors contains several distinct protein motifs. The filled circles represent cysteine-rich regions separated by a fi-bronectin type-III repeat.The open circles to the right of the line contain Ig-like loops and the sphere-filled rectangle on the intracellular portion of the receptor contains the catalytic tyrosine kinase domain which is activated upon interaction of the extracellular portion of the receptor with the cognate ligand. Activation of the tyrosine kinase leads to activation of other signaling paths including the MAPK path,the PLCg path,and the PI-3 kinase paths that ultimately transmit signals to the nucleus regulating gene transcription and ultimately affecting cell survival,growth,and differentiation.

Figure 15.1

2004). The NT/Trk (Kaplan and Miller 2000),p75 and the membrane bound kinase receptors of glial-de-rived neurotrophic factors (GDNF/RET), play important roles in the development of the peripheral nervous system.

The majority of migrating neural crest cells express TrkC and p75 and may be mitotically active or post-mitotic. A fraction of these also co-express TrkA. In the adrenal gland. The BDNF is expressed in the adrenal cortex during embryogenesis but is restricted to the interface of the adrenal cortex and medulla in the adult. Another TrkB ligand, NT-4, is highly expressed in the adrenal medulla. The majority of neuronal cells in the medulla express TrkA and p75 but not TrkB, although TrkB is restricted to a small number of ganglion cells. Under certain conditions NT-4 activates TrkA and may serve as a physiologic ligand for TrkA expressing chromaffin cells; however the neurons of the intermediolateral column of the spinal cord express TrkB and BDNF and innervate adrenal medullary chromaffin cells (Schober et al. 1999).

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