A novel axon guidance mechanism

[Introduction|Part 3|Part 4]

Lopez-Bendito et al (2006) show that pathfinding of thalamocortical axons (TCAs) requires the formation of a permissive corridor through non-permissive territory, and that this corridor is generated by cells which undergo a tangential migration from the lateral ganglionic eminence (LGE).

TCAs arise in the dorsal thalamus, and follow a stereotyped pathway into the developing neocortex. Initially, they are repelled by Slit 1 and Slit 2 expressed in the hypothalamus. They extend rostrally into the telencephalon and turn sharply before extending dorsolaterally to enter the medial ganglionic eminence (MGE). They then extend through the developing striatum and into the neocortex (see Figure 1).

Figure 1. Schematic diagram showing how tangential neuronal migration forms a permissive corridor through which thalamocortical axons (TCAs) extend. TCAs (red) originate in the dorsal thalamus and extend rostroventrally into the developing telencephalon. At embryonic day (E) 12.5 in the mouse, an unidentified chemorepellant (purple) prevents TCAs from entering the medial ganglioic eminence (MGE). Islet1+ interneurons migrate from the lateral ganglionic eminence (LGE) into the MGE. By E13.5, the LGE-derived neurons have generated a permissive corridor, which TCAs use to extend through the MGE. Corridor cells express NRG1 (green crosses), which contributes to the navigation of TCAs. The developing neocortex also expresses NRG1, which may be required for the final stage of TCA pathfinding. (Adapted from Lopez-Bendito et al, 2006.)

Using antibody staining, López-Bendito et al found that corridor cells express the LGE markers Islet1, Ebf1 and Meis2, suggesting that they are derived from the LGE. Corridor cells were also found to express Gad67, further suggesting that they are GABAergic interneurons.

LGE ventricular zone tissue from transgenic mice expressing green fluorescent protein (GFP) was then transplanted into its corresponding location in brain slices from wild-type (WT) mice of the same age. Fluorescence microscopy revealed the presence of GFP+ cells in the MGE, with a morphology characteristic of tangentially migrating neurons. When a semi-permeable membrane between the LGE and MGE blocked the ventral migration of Islet1+ cells, and prevented formation of the permissive corridor.

LGE-derived corridor cells were found to express two different membrane-bound isoforms of Neuregulin1 (CRD-NRG1 and NRG1 Type III), so the role of these proteins was investigated. TCAs were diverted from their normal path by aggregates of COS cells expressing CRD-NRG1 placed just ventral to the site at which they first enter the MGE. DiI-labelling revealed that TCA pathfinding is aberrant in CDR-NRG1 knockout mice: the axons reach the MGE as normal, but extend through randomly. Embryos lacking the NRG1 receptor ErbB4 displayed a similar phenotype.

In Mash1 mutant embryos, tangential migrations in the telencephalon are severly disrupted. In situ hybridization with probes for Ebf1 showed that the corridor did not form in Mash1 mutants, and DiI labelling of the dorsal thalamus in cultured telencephalon slices showed that TCAs failed to extend into the MGE. However, when wild-type LGE tissue was transplanted into slices from mutants, the corridor formed and TCA extension was rescued.

All these data support the hypothesis that LGE-derived interneurons form a permissive corridor through which TCAs extend, and that corridor cells express CDR-NRG1 and NRG1 Type III, which are involved in TCA navigation. These cells migrate ventrally, and are distinct from the interneurons which migrate dorsally from the LGE into the neocortex.

Reference:

Lopez-Bendito, G., Cautinat, A., Sanchez, J. A., Bielle, F., Flames, N., Garrat, A. N., Talmage, D. A., Role, L. W., Charnay, P., Marin, O. & Garel, S. (2006). Tangential neuronal migration controls axon guidance: A role for Neuregulin-1 in thalamocortical axon navigation. Cell 125: 127-142.