Transcriptional Regulation of Axon Pathfinding

The identification of the transcription factors involved in regulating axon pathfinding is far from complete. One important task for the near future of this field is to identify more transcriptional regulators of axon pathfinding. As we learn more about the nature of these transcription factors, it will be of interest to determine the level of control they exert over the pathway choices of an axon. That is, how directly is transcriptional regulation involved in the dynamic expression patterns that have been demonstrated for certain outgrowth and pathfinding related molecules? Expression of some surface proteins on axons is regulated with exquisite spatial and temporal detail at important decision points during axon outgrowth. For example, in the embryonic rat spinal cord, commissural neurons express TAG-1 while they are extending in the circumferential pathway toward the ventral midline. After the axons cross the midline, they turn abruptly and project in the longitudinal plane. Crossing the midline is associated with the downregulation of TAG-1 on the axons and upregulation of another cell-surface glycoprotein, L1. L1 is specifically expressed on the contralateral axon segment but is never expressed on the ipsilateral segment, cell bodies or dendrites of commissural neurons (Dodd et al. 1988xDodd, J, Morton, S.B, Karagogeos, D, Yamamoto, M, and Jessell, T.M. Neuron. 1988; 1: 105–116Abstract | Full Text PDF | PubMed | Scopus (504)See all ReferencesDodd et al. 1988). Likewise, in the grasshopper and in Drosophila, certain axonal glycoproteins are also selectively expressed in discrete segments of individual axons (2xBastiani, M.J, Harrelson, A.L, Snow, P.M, and Goodman, C.S. Cell. 1987; 48: 745–755Abstract | Full Text PDF | PubMed | Scopus (217)See all References, 10xPatel, N.H, Snow, P.M, and Goodman, C.S. Cell. 1987; 48: 975–988Abstract | Full Text PDF | PubMed | Scopus (356)See all References).In each of these cases, it is not known whether the switch in glycoprotein expression is cell autonomous or whether it is induced by external cues. If it occurs in response to an environmental stimulus the question remains, do transcription factors promote transcription of new message in anticipation of, or in response to the encounter with the stimulus? The latter case implies that a signal is sent from the growth cone back to the cell body altering transcription in the nucleus. However, some growth cones can navigate normally in vivo for several hours after being disconnected from their somas (e.g.,Harris et al. 1987xHarris, W.A, Holt, C.E, and Bonhoeffer, F. Development. 1987; 101: 123–133PubMedSee all ReferencesHarris et al. 1987). Indeed, the distance from the growth cone to the nucleus can be quite large, raising the question of whether this retrograde signaling mechanism is feasible given the current understanding of axonal transport and signaling mechanisms. Thus, transcriptional regulation of pathfinding cues is more likely to occur in advance of guidance cue encounters by growth cones. In this scenario, encounters with axon guidance cues would induce local changes in axonal proteins by one of two methods: either by post-translational alterations in proteins already present in the growth cone or by activating translation of previously transcribed messages located in growth cones or distal axons. Elucidating the signal transduction pathways activated in response to external guidance cues will tell us whether one or both of these mechanisms are at work.The recent identification of transcriptional regulators of axonal projection is an exciting advance that raises interesting questions about the role of transcriptional regulation in axon pathfinding. Primary among them is how tightly regulated are the pathfinding choices of an axon? Does there exist a single transcription factor that can turn on the expression of all of the various receptors and intracellular signaling molecules necessary for an axon to read a particular environment and the positive and negative cues that contribute to guide the growth cone to its appropriate target? Are there combinations of such factors that vary for slightly different projection subtypes (such as suggested in vertebrate motor neurons)? And how much feedback regulation of transcription is plausible from the environment encountered by the growth cone itself? An important challenge will be to determine the genes that are regulated by pathfinding-related transcription factors. This will help to shed light on the precise role of transcriptional regulation in axon pathfinding and will surely lead to the identification of new important players in the regulation of pathway choice and target recognition.