Progenitors within the ventral telencephalon can generate GABAergic neurons and oligodendrocytes, but regulation of the neuron-glial switch is poorly understood. We investigated the combinatorial expression and function of Dlx1&2, Olig2, and Mash1 transcription factors in the ventral telencephalon. We show that Dlx homeobox transcription factors, required for GABAergic interneuron production, repress oligodendrocyte precursor cell (OPC) formation by acting on a common progenitor to determine neuronal versus oligodendroglial cell fate acquisition. We demonstrate that Dlx1&2 negatively regulate Olig2-dependant OPC formation and that Mash1 promotes OPC formation by restricting the number of Dlx+ progenitors. Progenitors transplanted from Dlx1&2 mutant ventral telencephalon into newborn wild-type mice do not produce neurons but differentiate into myelinating oligodendrocytes that survive into adulthood. Our results identify another role for Dlx genes as modulators of neuron versus oligodendrocyte development in the ventral embryonic forebrain.

The subventricular zone (SVZ) of the postnatal brain continuously generates olfactory bulb (OB) interneurons. We show that calretinin ϩ , calbindin ϩ , and dopaminergic (TH

Summary The bHLH transcription factors that regulate early development of the central nervous system can generally be classified as either anti-neural or pro-neural. Initial expression of anti-neural factors prevents cell cycle exit and thereby expands the pool of neural progenitors. Subsequent (and typically transient) expression of pro-neural factors promotes cell cycle exit, subtype specification and differentiation. Against this backdrop, the bHLH transcription factor Olig2 in the oligodendrocyte lineage is unorthodox, showing anti-neural functions in multipotent CNS progenitor cells but also sustained expression and pro-neural functions in formation of oligodendrocytes. We show here that the proliferative function of Olig2 is controlled by developmentally regulated phosphorylation of a conserved triple serine motif within the amino terminal domain. In the phosphorylated state, Olig2 maintains anti-neural (i.e. pro-mitotic) functions that are reflected in human glioma cells and in a genetically defined murine model of primary glioma.

DLX1 and DLX2 transcription factors are necessary for forebrain GABAergic neuron differentiation, migration, and survival. We generated transgenic mice that express Cre-recombinase under the control of two ultra-conserved DNA elements near the Dlx1&2 locus termed I12b and URE2. We show that Cre-recombinase is active in a “Dlx-pattern” in the embryonic forebrain of transgenic mice. I12b-Cre is more active than URE2-Cre in the medial ganglionic eminences and its derivatives. Fate-mapping of EGFP+ cells in adult Cre;Z/EG animals demonstrated that GABAergic neurons, but not glia, are labeled. Most NPY+, nNOS+, parvalbumin+, and somatostatin+ cells are marked by I12b-Cre in the cortex and hippocampus, while 25-40% of these interneuron subtypes are labeled by URE2-Cre. Labeling of neurons generated between E12.5 to E15.5 indicated differences in birth-dates of EGFP+ cells that populate the olfactory bulb, hippocampus, and cortex. Finally, we provide the first in vivo evidence that both I12b and URE2 are direct targets of DLX2 and require Dlx1 and Dlx2 expression for proper activity.

Stimulation of m1 and m3 muscarinic acetylcholine receptors, which are coupled to phosphoinositide hydrolysis and protein kinase C activation, has been shown to increase the release of soluble amyloid precursor protein derivatives (APPs). The effect is mimicked by phorbol esters, which directly activate protein kinase C. Using human embryonic kidney cells expressing individual muscarinic receptor subtypes, we found that stimulation of APPs release by the muscarinic agonist carbachol was only partially reduced by a specific inhibitor of protein kinase C (the bisindolylmaleimide GF 109203X), while the response to phorbol 12-myristate 13-acetate (PMA) was abolished. The increase in APPs release elicited by carbachol and PMA was accompanied by elevated tyrosine phosphorylation of several proteins and reduced by tyrosine kinase inhibitors; GF 109203X significantly reduced the stimulation of tyrosine phosphorylation by carbachol and PMA. Inhibition of protein tyrosine phosphatases by vanadyl hydroperoxide markedly increased cellular tyrosine phosphorylation and enhanced APPs release as effectively as PMA and carbachol. Direct phosphorylation of amyloid precursor protein on tyrosine residues following treatment with carbachol, PMA, or vanadyl hydroperoxide was not observed. The results implicate both tyrosine phosphorylation and protein kinase C-dependent mechanisms in the regulation of APPs release by G protein-coupled receptors, and suggest that carbachol and PMA increase APPs release from human embryonic kidney cells expressing m3 muscarinic receptors via partially divergent pathways that converge at a tyrosine phosphorylation-dependent step.

Krabbe disease is a devastating pediatric leukodystrophy caused by mutations in the galactocerebrosidase (GALC) gene. A significant subset of the infantile form of the disease is due to missense mutations that result in aberrant protein production. The currently used mouse model, twitcher, has a nonsense mutation not found in Krabbe patients, although it is similar to the human 30 kb deletion in abrogating GALC expression. Here, we identify a spontaneous mutation in GALC, GALCtwi-5J, that precisely matches the E130K missense mutation in patients with infantile Krabbe disease. GALCtwi-5J homozygotes show loss of enzymatic activity despite normal levels of precursor protein, and manifest a more severe phenotype than twitcher, with half the life span. Although neuropathological hallmarks such as gliosis, globoid cells and psychosine accumulation are present throughout the nervous system, the CNS does not manifest significant demyelination. In contrast, the PNS is severely hypomyelinated and lacks large diameter axons, suggesting primary dysmyelination, rather than a demyelinating process. Our data indicate that early demise is due to mechanisms other than myelin loss and support an important role for neuroinflammation in Krabbe disease progression. Furthermore, our results argue against a causative relationship between psychosine accumulation, white matter loss and gliosis.

Neuroinflammation, activation of innate immune components of the nervous system followed by an adaptive immune response, is observed in most leukodystrophies and coincides with white matter pathology, disease progression, and morbidity. Despite this, there is a major gap in our knowledge of the contribution of the immune system to disease phenotype. Inflammation in Krabbe's disease has been considered a secondary effect, resulting from cell-autonomous oligodendroglial cell death or myelin loss resulting from psychosine accumulation. However, recent studies have shown immune activation preceding clinical symptoms and white matter pathology. Moreover, the therapeutic effect underlying hematopoietic stem cell transplantation, the only treatment for Krabbe's disease, has been demonstrated to occur via immunomodulation. This Review highlights recent advances in elaboration of the immune cascade involved in Krabbe's disease. Mechanistic insight into the inflammatory pathways participating in myelin and axon loss or preservation may lead to novel therapeutic approaches for this disorder.

The leukodystrophies are a heterogeneous, often progressive group of disorders manifesting a wide range of symptoms and complications. Most of these disorders have historically had no etiologic or disease specific therapeutic approaches. Recently, a greater understanding of the pathologic mechanisms associated with leukodystrophies has allowed clinicians and researchers to prioritize treatment strategies and advance research in therapies for specific disorders, some of which are on the verge of pilot or phase I/II clinical trials. This shifts the care of leukodystrophy patients from the management of the complex array of symptoms and sequelae alone to targeted therapeutics. The unmet needs of leukodystrophy patients still remain an overwhelming burden. While the overwhelming consensus is that these disorders collectively are symptomatically treatable, leukodystrophy patients are in need of advanced therapies and if possible, a cure.