Most of the inhibitory interneurons of the cerebral cortex originate in the medial ganglionic eminence (MGE), one of the subdivisions of the subcortical telencephalon. From the MGE, they migrate tangentially (parallel to the brain surface) to colonize the cortex. The migrating cells are thought to be kept on track by a combination of repulsive and attractive cues, but until recently, only chemorepellants had been described. Now, in a study reported in Neuron, Flames and colleagues identify Neuregulin-1 (NRG1) as the first candidate for the chemoattractant role.

Schematic diagram of the embryonic day 13.5 mouse brain, showing routes of migration for cells derived from the medial ganglionic eminence.

There are three main isoforms of NRG1: Types I and II (collectively known as NRG1-Ig), which are secreted, and Type III (also known as NRG1-CRD), which is membrane-bound. Flames et al. showed that Nrg1-CRD mRNA is expressed in a 'corridor' through the lateral ganglionic eminence that corresponds to the migration pathway of cortical interneurons. When faced with the choice of migrating on Nrg1-CRD-expressing or -non-expressing cells, MGE cells were around twice as likely to choose the Nrg1-CRD-expressing cells, and the authors propose that NRG1-CRD provides a permissive substrate for interneuron migration.

The expression pattern of NRG1-Ig is consistent with the idea that it functions as a diffusible chemoattractant. At the developmental stage when interneurons first begin to enter the cortex, Nrg1-Ig is expressed at higher levels in more lateral cortical regions, but its expression spreads medially as development proceeds, mirroring the advancing front of migrating interneurons. Flames et al. showed that MGE cells were attracted towards a source of NRG1-Ig in culture, and in brain slices, a graft of NRG1-Ig-expressing cells in the ventrolateral telencephalon could attract MGE cells and divert them from their usual migration course.

The NRG1 receptor ERBB4 is expressed in a subpopulation of MGE-derived cells, and the authors asked whether the attractive effects of NRG1 are mediated through this receptor. They found that expression of a dominant negative form of ERBB4 (dnErbB4) in cultured MGE cells rendered these cells almost completely unresponsive to the attractive effects of a cortical tissue explant. In brain slices, dnErbB4-expressing MGE cells accumulated in the basal telencephalon instead of migrating to the cortex. Also, knockout mice that lacked either ErbB4 or Nrg1 showed decreased numbers of inhibitory interneurons in the cortex.

Flames et al. conclude that different isoforms of NRG1 act at short and long range to guide MGE-derived interneurons towards the cortex, and that this chemoattraction is mediated by ERBB4. However, as not all MGE-derived cells express ERBB4, it is probable that more chemoattractants for cortical interneurons are waiting to be discovered.