Tumors of the same histologic type often comprise clinically and molecularly distinct subgroups; however, the etiology of these subgroups is unknown. Here, we report that histologically identical, but genetically distinct, ependymomas exhibit patterns of gene expression that recapitulate those of radial glia cells in the corresponding region of the central nervous system. Cancer stem cells isolated from ependymomas displayed a radial glia phenotype and formed tumors when orthotopically transplanted in mice. These findings identify restricted populations of radial glia cells as candidate stem cells of the different subgroups of ependymoma, and they support a general hypothesis that subgroups of the same histologic tumor type are generated by different populations of progenitor cells in the tissues of origin.

Central norepinephrine producing neurons comprise a diverse population of cells differing in anatomical location, connectivity, function and response to disease and environmental insult. At present, the mechanisms that generate this diversity are unknown. Here we elucidate the lineal relationship between molecularly distinct progenitor populations in the developing mouse hindbrain and mature norepinephrine neuron subtype identity. We have identified four genetically separable subpopulations of mature norepinephrine neurons differing in their anatomical location, axon morphology and efferent projection pattern. One of the subpopulations revealed an unexpected projection to the prefrontal cortex, challenging the long-held belief that the locus coeruleus (LoC) is the sole source of norepinephrine projections to the cortex. These findings reveal the embryonic origins of central norepinephrine neurons and provide for the first time multiple molecular points of entry for future study of individual norepinephrine circuits in complex behavioral and physiological processes including arousal, attention, mood, memory, appetite, and homeostasis.

Central serotonin (5-HT, 5-hydroxytryptamine)-producing neurons are heterogeneous, differing in location, morphology, neurotoxin sensitivity and associated developmental disorders such as sudden infant death syndrome, fetal alcohol syndrome, and autism. Yet the molecular underpinnings associated with such heterogeneity and differential disease vulnerability are largely unknown, as are molecular markers capable of identifying physiological subtypes of 5-HT neurons. Here we redefine subtypes within the mature 5-HT system based on genetic programs differentially enacted and differentially required in progenitor cells. We present a molecular framework for the 5-HT neural system that, having genetic lineages as its basis, is likely to have physiological relevance and will provide a means for selectively accessing 5-HT neurons for in vivo manipulations.Abnormalities in 5-HT-producing neurons are increasingly implicated in a broad spectrum of developmental disorders, including sudden infant death syndrome 1 , fetal alcohol syndrome 2 , and autism (reviewed in 3 ). Each disorder differs in clinical feature, and mounting evidence suggests that different 5-HT neuron subtypes are selectively affected. Heterogeneity within the 5-HT neuron population is further demonstrated by differences in anatomical distribution, cell morphology and axonal trajectory, neurotoxin sensitivity and physiological properties (reviewed in 4 ). Mechanisms that determine these differences are largely unknown and presently few molecular markers have been identified which are capable of distinguishing individual 5-HT neuron subtypes. Such knowledge is central to understanding etiological differences among 5-HT neuron disorders and for gaining genetic access to select 5-HT neuron subgroups for experimental study.While markers capable of distinguishing mature 5-HT neuron subtypes are wanting, at hand are markers that, when viewed in combinations, can resolve 5-HT progenitor cells into discrete subsets. From these subsets may arise physiologically relevant groupings of mature 5-HT neurons; this is because developmental programs that define the fate and function of neurons are often set in motion by the action of factors differentially expressed among their antecedent * to whom correspondence should be addressed: Telephone: 617-432-4812, Facsimile: 617-432-7595, dymecki@genetics.med.harvard.edu. † these authors contributed equally Competing Interests StatementThe authors declare that they have no competing financial interests. NIH Public AccessAuthor Manuscript Nat Neurosci. Author manuscript; available in PMC 2010 July 6. This progenitor territory can be subdivided along the AP axis into molecularly distinct subsets based on the broader partitioning of the hindbrain into segments (rhombomeres) with distinguishing gene expression profiles (reviewed in 5 ). Thus, aspects of 5-HT neuron subtype identity may be determined through the action of rhombomere(r)-specific genetic programs on resident 5-HT progenitor and precursor cell subsets. We have se...

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