Ventral telencephalic progenitors expressing the homeodomain transcription factor Nkx6-2 have been shown to give rise to a multitude of cortical interneuron subtypes usually associated with origin in either the medial ganglionic eminence or the caudal ganglionic eminence. The function of Nkx6-2 in directing the fate of those progenitors has, however, not been thoroughly analyzed. We used a combination of genetic inducible fate mapping and in vivo loss-of-function to analyze the requirement of Nkx6-2 in determining the fate of cortical interneurons. We have found that interneuron subtypes are born with a characteristic temporal pattern. Furthermore, we extend the characterization of interneurons from the Nkx6-2 lineage through the application of electrophysiological methods. Analysis of these populations in Nkx6-2 null mice suggests that there is a small and partially penetrant loss of delayed non-fast spiking somatostatin/calretinin double positive cortical interneurons in the absence of Nkx6-2 gene function.

Complex and precisely orchestrated genetic programs contribute to the generation, migration, and maturation of cortical GABAergic interneurons (cIN). Yet, little is known about the signals that mediate the rapid alterations in gene expression that are required for cINs to transit through a series of developmental steps leading to their mature properties in the cortex. Here, we investigated the function of post-transcriptional regulation of gene expression by microRNAs on the development of cIN precursors. We find that conditional removal of the RNAseIII enzyme Dicer reduces the number of cINs in the adult mouse. Dicer is further necessary for the morphological and molecular maturation of cINs. Loss of mature miRNAs affects cINs development by impairing migration and differentiation of this cell type, while leaving proliferation of progenitors unperturbed. These developmental defects closely matched the abnormal expression of molecules involved in apoptosis and neuronal specification. In addition, we identified several miRNAs that are selectively upregulated in the postmitotic cINs, consistent with a role of miRNAs in the post-transcriptional control of the differentiation and apoptotic programs essential for cIN maturation. Thus, our results indicate that cIN progenitors require Dicer-dependent mechanisms to fine-tune the migration and maturation of cINs.

At present little is known about the developmental mechanisms that give rise to inhibitory gamma-aminobutyric acidergic interneurons of the neocortex or the timing of their subtype specification. As such, we performed a gene expression microarray analysis on cortical interneuron precursors isolated through their expression of a Dlx5/6(Cre-IRES-EGFP) transgene. We purified these precursors from the embryonic mouse neocortex at E13.5 and E15.5 by sorting of enhanced green fluorescent protein-expressing cells. We identified novel transcription factors, neuropeptides, and cell surface genes whose expression is highly enriched in embryonic cortical interneuron precursors. Our identification of many of the genes known to be selectively enriched within cortical interneurons validated the efficacy of our approach. Surprisingly, we find that subpopulations of migrating cortical interneurons express genes encoding for proteins characteristic of mature interneuron subtypes as early as E13.5. These results provide support for the idea that many of the genes characteristic of specific cortical interneuron subtypes are evident prior to their functional integration into cortical microcircuitry. They suggest interneurons are already relegated to specific genetic subtypes shortly after they become postmitotic. Moreover, our work has revealed that many of the genes expressed in cortical interneuron precursors have been independently linked to neurological disorders in both mice and humans.