Genetic programs controlling cortical interneuron fate

Abstract

The origins of cortical interneurons in rodents have been localized to the embryonic subcortical telencephalon where distinct neuroepithelial precursors generate defined interneuron subsets. A swathe of research activity aimed at identifying molecular determinants of subtype identity has uncovered a number of transcription factors that function at different stages of interneuron development. Pathways that lead to the acquisition of mature interneuron traits are therefore beginning to emerge. As genetic programs are influenced by external factors the search continues not only into genetic determinants but also extrinsic influences and the interplay between the two in cell fate specification.

Figure 1

Embryonic origin and mature fates of cortical interneurons. (a) Schematic showing the subdivisions of the embryonic telencephalon. The three regions where cortical and hippocampal interneurons originate are the medial ganglionic eminence (MGE) (including the dorsal MGE-dMGE), the caudal ganglionic eminence (CGE) and the preoptic area (POA). The dorsal part of the CGE (dCGE) is a caudal extension of the lateral ganglionic eminence (LGE) and is distinct from the MGE. These progenitor zones of the telencephalon can be identified by combinatorial expression of transcription factors within the neuroepithelium. (b) The major classes of cortical interneurons that originate from the three neuroepithelial regions during embryogenesis can be identified using neurochemical markers. The MGE generates 60% of all cortical interneurons and includes mainly parvalbumin (PV)-expressing and somatostatin (SST)-expressing subtypes. A large fraction of the SST cells co-express reelin (RLN). SST/calretinin (CR) co-expressing interneurons are derived exclusively from the dMGE. The POA generates ∼10% of all cortical interneurons and includes a variety of subtypes. The dCGE is the source of ∼30% of all cortical interneurons. Half of these co-express RLN and smaller fractions express vasoactive intestinal peptide (VIP) and/or CR. Note that neuropeptide Y (not shown in the figure) is also expressed in subsets of cortical interneurons, including ones derived from the POA. (c) Distribution of MGE (red)-derived, POA (blue)-derived and dCGE (green)-derived interneuron populations within the different layers (I–VI) of the adult cortex.

Figure 2

Genetic programs controlling cortical interneuron development. (a) Progressive stages of cortical interneuron development. (b) Cortical interneuron development from the three major telencephalic sources: the MGE, the dCGE and the POA. Transcription factors involved at different stages of cortical interneuron development are shown. Some of these factors participate broadly in interneuron development (e.g. members of the DLX and NR2F families and ARX). ZEB2 has been described in the MGE lineage but may also be expressed in other interneuron populations. Other transcription factors are unique to specific domains and/or stages of differentiation: NKX2-1 defines the MGE neuroepithelium and activates a cascade of genes downstream including Lhx6, Sox6 and Satb1; NKX6-2 and GLI1 are enriched in the neuroepithelium of the dMGE (although not restricted to that region) and provide this domain with its unique identity and differentiation potential; DBX1 and HMX3 have been used to fate-map the POA because of their restricted expression in this domain; PROX1 and SP8 have been identified as being expressed in CGE-derived cortical interneurons at all stages of their development. Although depicted as having common precursors, interneurons that originate from the same neuroepithelial domain may arise from lineages that split early during development. Note that the VZ of the dMGE expresses MGE transcription factors in addition to the dMGE-specific genes indicated. ? indicates that expression is unclear or unknown. * indicates expression in some but not all cells. Expression of Zeb2, Sox6 and Satb1 has not been examined in POA-derived cortical interneurons.