1 is the only known factor specifically expressed within MGE by all progenitors in the ventricular zone (VZ) and subventricular zone (SVZ) (Flames et al.,
2007 and Marín and Rubenstein, 2001). In addition, Lhx6 and Er81 are expressed in subdomains of MGE and CGE (Figure 2A) (Flames et al., 2007 and Butt et al., 2008). We have generated inducible CreER drivers targeting these transcription factor genes (see Table 1 and Table 2). Although several Nkx2.1 transgenic lines have been generated expressing a constitutive Afatinib chemical structure form of Cre (Fogarty et al., 2007 and Xu et al., 2008), they deviate from the spatiotemporal pattern of endogenous Nkx2.1 to varying degrees, and offer no temporal control over Cre activity. In contrast, our Nkx2.1-CreER driver appeared to precisely recapitulate the endogenous expression and allows temporal regulation of Cre activity, thereby establishing reliable genetic access to the MGE progenitors ( Figure 2). E12 tamoxifen induction resulted in robust labeling of the VZ and SVZ progenitors in MGE and POA but not lateral ganglionic eminence (LGE) ( Figures 2B and 2C). Low-dose tamoxifen induction (0.5 mg/30 g body weight) further revealed radial columns of cells, which likely represent putative
progenitor clones in MGE ( Figure 2D). Consistent with previous studies ( Miyoshi et al., 2007), E12 induction gave rise to cortical GABA neurons expressing parvalbumin (PV), somatostatin (SST), but not vasoactive intestinal peptide (VIP) ( Figures 2J–2L). Recent studies demonstrate Selleck Ixazomib that Nkx2.1 expression continues beyond mid-gestation and persists the in the ventral ridge of SVZ during late embryonic and postnatal ages (Marin et al., 2000 and Magno et al., 2009). Indeed,
we found Nkx2.1-Cre activity in ventral SVZ beyond E17 ( Figures 2E–2G), when the characteristic eminence of MGE had already fused with the adjacent LGE. This raised the issue of whether these ventral SVZ cells derived from earlier MGE or acquired Nkx2.1 expression independently. We found that these Nkx2.1+ cells continued to incorporate BrdU labeling at E17 (administered 4 times every 4 hr) and thus retained mitotic competence, which is a key indication of progenitor properties. Using genetic fate mapping, we further demonstrated that Nkx2.1+ progenitors in ventral SVZ derived from earlier progenitors in MGE (e.g., from E12 MGE progenitors; Figures 2H and 2I) but not the LGE. Members of the Dlx family of homeobox transcription factors, Dlx1, Dlx2, Dlx5, and Dlx6, are expressed mainly in the SVZ of embryonic LGE, MGE, and CGE (Eisenstat et al., 1999). Dlx genes continue to express in subsets of GABAergic neurons in embryonic, postnatal, and mature brains, and have been implicated in regulating their migration, differentiation, survival, and function ( Cobos et al., 2005, Cobos et al., 2007 and Long et al., 2009). Whether and how different members control the development and function of subpopulations of interneurons is not well understood.