Developmental Signalling

Abstract

1. In investigating the communication paths between target tissue and neurons we have been led to propose two classes of neurotrophic factors. One comprises the factors which transport themselves, the other factors relying on the transport of a second messenger. The former may have labile second messenger systems necessitating the translocation of agonist and receptor from the nerve terminal to the cell body and the latter must possess a stable second messenger system that itself is sufficiently robust to survive the transport to the cell body. 2. One such class of stable messengers may be the GTP-binding protein family and it has been shown that the alpha subunits of both Gi alpha and Gz alpha can be retrogradely transported in the mouse sciatic nerve. 3. Examination of the cell bodies in the dorsal root ganglia revealed that Gz alpha accumulated in the nucleus of cells with intact axons but that 24 h after axonal ligation this immunoreactivity decreased. 4. It is suggested that Gz is activated at the nerve terminal and it, or at least its alpha subunit, undergoes retrograde transport to the cell body where it accumulates in the nucleus.

Signalling organelle for retrograde axonal transport of internalized neurotrophins from the nerve terminal

“…The retrograde transport process itself follows this. When the active complex arrives at the cell body, it must generate the appropriate second messenger cascade to signal to the nucleus 15 . This paper looks in more detail at the steps of receptor binding and internalization and the resultant structural correlate of the retrograde signal.…”

“…It has been suggested that, in the adult mammalian nervous system, a cascade of activated tyrosine receptor kinase (Trk) receptors may function as rapid retrograde signal carriers 12 , 13 . However, it is more likely that the neurotrophins stimulate retrograde transport of the activated Trks, bound to their cognate ligand, to transmit this information 14 by delivering an activated receptor to the cell body 15 …”

Structure and Function of the Pertussis-Toxin-Insensitive G_z Protein

“…Both orthograde and retrograde axonal transports of · z have been detected through ligation experiments using sensory sural nerve, sciatic nerve and dorsal root ganglion [59,63]. The retrograde axonal transport of · z targets to the nuclei of the neurons [64,65], which implies the retrograde signals carried by · z may have nuclear functions. It may also correlate to the transformation properties of activated · z mutant in fibroblasts [52] and · z can somehow regulate certain gene expression events.…”

Comparison of nerve terminal events in vivo effecting retrograde transport of vesicles containing neurotrophins or synaptic vesicle components

“…Neurons that receive sufficient amounts of neurotrophin (NT) via retrograde axonal transport survive and form synapses whereas those neurons that do not are removed by developmentally programmed cell death (Hendry et al, 1973; Purves, 1988; Barde, 1989; Oppenheim et al, 1991; Raff, 1992). The finding that nerve growth factor (NGF) was transported in vesicles (Schwab, 1977) and that intracytoplasmic NGF was functionally inactive (Heumann et al, 1981) has led to a contemporary model in which retrograde NT transport occurs in vesicles containing growth factor in the lumen and receptor in the membrane transported as a signaling complex that can activate appropriate second messenger cascades at the soma (Hendry et al, 1995; Reynolds et al, 2000; Weible et al, 2001). The vesicular‐based mechanism for transport of the retrograde signal has been substantiated by extensive work showing NGF and activated TrkA receptor contained in crude endosomal fractions (Grimes et al, 1996, 1997), and these endosomes include activated signaling proteins (Delcroix et al, 2003).…”