Lhx6Activity Is Required for the Normal Migration and Specification of Cortical Interneuron Subtypes

Abstract

The cerebral cortex contains two main neuronal cell populations, the excitatory glutamatergic (pyramidal) neurons and the inhibitory interneurons, which synthesize GABA and constitute 20 -30% of all cortical neurons. In contrast to the mostly homogeneous population of projection neurons, cortical interneurons are characterized by remarkable morphological, molecular, and functional diversity. Among the markers that have been used to classify cortical interneurons are the calcium-binding proteins parvalbumin and calretinin and the neuropeptide somatostatin, which in rodents identify mostly nonoverlapping interneuron subpopulations. Pyramidal neurons are born during embryogenesis in the ventricular zone of the dorsal telencephalon, whereas cortical interneurons are generated in the subpallium and reach the cortex by tangential migration. On completion of tangential migration, cortical interneurons switch to a radial mode of migration and enter the cortical plate. Although the mechanisms that control the generation of interneuron diversity are currently unknown, it has been proposed that their site of origin in the ventral forebrain determines their specification into defined neurochemical subgroups. Here, we show that Lhx6, a gene induced in the medial ganglionic eminence and maintained in parvalbumin-and somatostatin-positive interneurons, is required for the specification of these neuronal subtypes in the neocortex and the hippocampus. We also show that Lhx6 activity is required for the normal tangential and radial migration of GABAergic interneurons in the cortex.

Cxcr4 regulation of interneuron migration is disrupted in 22q11.2 deletion syndrome

“…Our previous work indicates that interneuron distribution is altered in the LgDel cortex, with an apparent shift of parvalbumin cells toward more superficial layers at the expense of deeper layers (18). To determine whether this defect is similar to those associated with other mutations that alter laminar distribution of interneurons (22,26,27), we evaluated the frequency and laminar distribution of molecularly distinct interneuron classes in the LgDel mouse. Among four subtypes, we found specific disruption of parvalbumin interneurons ( Fig.…”

“…Changes in the distribution of cortical interneurons have been associated with genetic mutations that disrupt the migration of these cells during early development (22,26,27). To determine whether migration of basal forebrain-derived interneurons into the cortical rudiment is indeed altered in the LgDel 22q11.2DS model, we used a Dlx5/6 Cre-IRES-eGFP (CIE) reporter mouse line that labels postmitotic neurons generated in the basal forebrain (29).…”

Transcription factor LIM homeobox 7 (Lhx7) maintains subtype identity of cholinergic interneurons in the mammalian striatum

“…"Terminal selector genes" encode transcription factors that coordinately regulate the expression of diverse molecular, morphological and functional characteristics that constitute the terminal phenotype of neurons (23). Lhx7 and Lhx6 belong to this class of genes because, respectively, they regulate multiple aspects of cholinergic and GABAergic interneuron differentiation in the mammalian forebrain (8,10,(12)(13)(14). In vertebrates terminal selector genes have been studied mostly in the context of lineage restriction and forward neuronal differentiation, but their subsequent role in maintaining neuronal subtype identity is largely unknown.…”

“…6). It should be noted that although the down-regulation of Lhx6 is crucial for cholinergic differentiation (8,10,(12)(13)(14), it is not sufficient for instructing cholinergic identity in interneuron precursors because Lhx6-null animals do not show an increase in the number of cholinergic interneurons. Accordingly, our observation in this report that the residual cholinergic neurons in Lhx7 mutants retain Isl1 but show subtle changes in morphology and expression of mature cholinergic markers suggests that Lhx7 (perhaps in combination with other factors such as Isl1) has additional roles in cholinergic differentiation.…”

“…Both GABAergic and cholinergic striatal interneurons (GSIs and CSIs, respectively) are derived from Nkx2.1-expressing progenitors of the medial ganglionic eminence (MGE) (6,7), which, upon exit from the cell cycle, express the LIM homeodomain (LIM HD) transcription factors LIM homeobox 6 (Lhx6) and LIM homeobox 7 (Lhx7) (8). A subset of these precursors maintains expression of Lhx6 and differentiate into mature GABAergic interneurons expressing the neuropeptide somatostatin (Sst) or the calcium-binding protein parvalbumin (Pv) (9,10). The remaining precursors induce expression of the LIM HD protein Isl1, down-regulate Lhx6, and differentiate into CSIs (8).…”