5 and E14.0 ( Figures 4 and S4; Table S1), which was very similar to the VZ defects found in the Lhx6PLAP/PLAP;Lhx8−/− mutant ( Figures 1 and S1). By E18.5, the progenitor zone phenotype in the Dlx1/2-cre;ShhF/− mutant appeared to be restricted to the rostrodorsal MGE. We propose that Lhx6/Lhx8-dependent Shh expression and secretion from neurons in the MGE MZ regulates the properties

Ibrutinib nmr of the overlying VZ. The Shh signaling may take place in the radial glial processes that interdigitate among the neurons, and/or through Shh diffusion to the VZ, where it would activate signaling in the neuroepithelial cell bodies. The ramifications of reducing Shh signaling in the dorsal MGE (based on reduced Gli1 and Ptc1 expression) include greatly reduced VZ expression of Nkx2-1 and Nkx6-2 and SVZ expression of Lhx6 and Lhx8 ( Figure 4, Figure 5 and Figure 6, S4, and S5). As discussed throughout this paper, Nkx2-1, Lhx6, and Lhx8 are required for the development of most MGE-derivatives. Nkx6-2 function is selleck required for generating a subset of SOM+;CR+ interneurons ( Sousa et al., 2009), and Gli1 (in conjunction with Gli2) is required in patterning the dorsal MGE and in generating cortical interneurons ( Yu et al., 2009). There is evidence that Shh dosage participates in the specification

of cortical interneuron subtypes. Exposing MGE explants to 10 nM SHH altered the distribution of interneuron fates that are present after transplantation

into a neonatal cortex; augmentation too of Shh-signaling increased SOM+ cells and reduced PV+ cells (Xu et al., 2010). This result led to the proposal that high SHH signaling promotes SOM fate over PV fate. However, this idea does not readily fit with fate mapping data showing that the dorsal MGE has the propensity to generate SOM+ neurons, whereas the ventral MGE, whose VZ has much higher Shh expression has the propensity to generate PV+ neurons (Flames et al., 2007, Wonders et al., 2008 and Flandin et al., 2010). The previous in vivo investigations into Shh regulation of interneuron development focused on Shh expression and function in the VZ; here, we addressed whether Shh expression in the MZ of the MGE controls interneuron development. In Dlx1/2-cre;ShhF/− mutant, consistent with the reduction in Lhx6 expression, we found reductions of SOM+ and PV+ cortical interneurons ( Figure 7). However, both subtypes were similarly reduced (∼40% in superficial layers and ∼20% in deep layers), failing to provide evidence that Shh expression in the MZ differentially regulated interneuron fate. Rather, these results support a model that Shh expression in the MZ, promotes SHH signaling in the dorsal MGE that then produces both SOM+ and PV+ cortical interneurons. On the other hand, Shh expression in the VZ of the ventral MGE and POA is critical for regulating development of these more ventral regions.