Serum response factor mediated gene activity in physiological and pathological processes of neuronal motility

Abstract

In recent years, the transcription factor serum response factor (SRF) was shown to contribute to various physiological processes linked to neuronal motility. The latter include cell migration, axon guidance, and, e.g., synapse function relying on cytoskeletal dynamics, neurite outgrowth, axonal and dendritic differentiation, growth cone motility, and neurite branching. SRF teams up with myocardin related transcription factors (MRTFs) and ternary complex factors (TCFs) to mediate cellular actin cytoskeletal dynamics and the immediate-early gene (IEG) response, a bona fide indicator of neuronal activation. Herein, I will discuss how SRF and cofactors might modulate physiological processes of neuronal motility. Further, potential mechanisms engaged by neurite growth promoting molecules and axon guidance cues to target SRF's transcriptional machinery in physiological neuronal motility will be presented. Of note, altered cytoskeletal dynamics and rapid initiation of an IEG response are a hallmark of injured neurons in various neurological disorders. Thus, SRF and its MRTF and TCF cofactors might emerge as a novel trio modulating peripheral and central axon regeneration.

Keywords: IEG; MRTF; SRF; TCF; axon; cytoskeleton; neurite; regeneration.

Figure 1

Comparison of SRF-deficient growth cones with retraction bulb. (A) Scheme of a growth cone of a wild-type neuron grown in cell culture. The growth cone typically protrudes multiple finger-like filopodia (one is marked by an arrow). (B) A growth cone derived from an SRF-deficient neuron grown in culture. Please note the reduced number of filopodia resulting in a round shape of the growth cone. (C) A so-called retraction bulb, typically found at the end of a transected axon of a wild-type neuron in vivo. Similar to SRF-deficiency (B), retraction bulbs elaborate fewer filopodia. Schematic drawing is based on a figure from Erturk et al. (2007).

Figure 2

Serum response factor signaling in neuronal motility. Summary of potential upstream signaling cascades activating SRF and/or TCF/MRTF cofactor activity. In addition, possible scenarios on the impact of SRF-mediated gene transcription on neuronal differentiation and axonal regeneration are provided. The latter include regulation of cell survival (e.g., via IEGs, neurotrophin, and insulin growth factors) and cytoskeletal dynamics. Here, SRF and most likely MRTFs will adjust mRNA levels of genes encoding cytoskeletal genes (gelsolin, actin isoforms, etc.) and modulate activity of the actin severing protein cofilin. Further, SRF might adjust Rho-GTPase activity and thereby modulate actin (and microtubule) polymerization.