During cerebral cortical development, excitatory glutamatergic projection neurons are generated from neural stem cells intrinsic to the early embryonic cortical ventricular zone by a process of radial migration, whereas most inhibitory ␥-aminobutyric acid (GABA)ergic interneurons and oligodendrocytes (OLs) appear to be elaborated from ventral forebrain stem cells that initially undergo tangential cortical migration before terminal lineage maturation. In contrast to the more compartmentalized developmental organization of the spinal cord, the generation of neurons and OLs from a common ventral forebrain stem cell would expose these cells to the sequential actions of ventral and dorsal gradient morphogens [sonic hedgehog (Shh) and bone morphogenetic proteins (BMPs)] that normally mediate opposing developmental programs. Here we report that Shh promotes GABAergic neuronal͞OL lineage restriction of forebrain stem cells, in part, by activation of the basic helix-loop-helix transcription factors, Olig2 and Mash1. In mutant mice with a generalized defect in tangential cortical migration (Dlx1͞2؊͞؊), there is a profound and selective reduction in the elaboration of both cortical GABAergic neurons and OLs. Our studies further demonstrate that the sequential elaboration of cortical GABAergic neurons and OLs from common Shh-responsive ventral forebrain progenitors requires the spatial and temporal modulation of cortical BMP signaling by BMP ligands and the BMP antagonist, noggin, respectively. These findings suggest an integrative model for cerebral cortical GABAergic neuronal and OL lineage maturation that would incorporate the sequential contributions of the ventral and dorsal forebrain, and the potential role of regional developmental cues in modulating transcriptional codes within evolving neural lineage species.

The pathogenesis of Huntington's disease (HD) remains elusive. The identification of increasingly early pathophysiological abnormalities in HD suggests the possibility that impairments of striatal medium spiny neuron (MSN) specification and maturation may underlie the etiology of HD. In fact, we demonstrate that HD knock-in (Hdh-Q111) mice exhibited delayed acquisition of early striatal cytoarchitecture with aberrant expression of progressive markers of MSN neurogenesis (Islet1, DARPP-32, mGluR1, and NeuN). Hdh-Q111 striatal progenitors also displayed delayed cell cycle exit between E13.5-15.5 (BrdU birth-dating) and an enhanced fraction of abnormal cycling cells in association with expansion of the pool of intermediate progenitors and over expression of the core pluripotency (PP) factor, Sox2. Clonal analysis further revealed that Hdh-Q111 neural stem cells (NSCs) displayed: impaired lineage restriction, reduced proliferative potential, enhanced late-stage self-renewal, and deregulated MSN subtype specification. Further, our analysis revealed that in addition to Sox2, the core PP factor, Nanog is expressed within the striatal generative and mantle regions, and in Hdh-Q111 embryos the fraction of Nanog-expressing MSN precursors was substantially increased. Moreover, compared to Hdh-Q18 embryos, the Hdh-Q111 striatal anlagen exhibited significantly higher levels of the essential PP cofactor, Stat3. These findings suggest that Sox2 and Nanog may play roles during a selective window of embryonic brain maturation, and alterations of these factors may, in part, be responsible for mediating the aberrant program of Hdh-Q111 striatal MSN specification and maturation. We propose that these HD-associated developmental abnormalities might compromise neuronal homeostasis and subsequently render MSNs more vulnerable to late life stressors. development ͉ huntingtin ͉ medium spiny neurons ͉ neurodegeneration

Recent studies have identified impairments in neural induction and in striatal and cortical neurogenesis in Huntington’s disease (HD) knock-in mouse models and associated embryonic stem cell lines. However, the potential role of these developmental alterations for HD pathogenesis and progression is currently unknown. To address this issue, we used BACHD:CAG-CreERT2 mice, which carry mutant huntingtin (mHtt) modified to harbor a floxed exon 1 containing the pathogenic polyglutamine expansion (Q97). Upon tamoxifen administration at postnatal day 21, the floxed mHtt-exon1 was removed and mHtt expression was terminated (Q97CRE). These conditional mice displayed similar profiles of impairments to those mice expressing mHtt throughout life: (i) striatal neurodegeneration, (ii) early vulnerability to NMDA-mediated excitotoxicity, (iii) impairments in motor coordination, (iv) temporally distinct abnormalities in striatal electrophysiological activity, and (v) altered corticostriatal functional connectivity and plasticity. These findings strongly suggest that developmental aberrations may play important roles in HD pathogenesis and progression.