High-throughput screening flows along.

mouse medulloblastomas, which are cerebel-lar tumors that, in humans, occur primarily between 5 and 10 years of age 7. Because the tumors spread through the CNS, treatment consists of surgical resection, radiation to the entire brain and spine, and chemotherapy and, as a consequence, leaves survivors with debili-tating learning and neuroendocrine hormonal deficiencies. A potential implication of this work is that neurotransmitter signaling might also sustain replicative potency of a medul-loblastoma stem or progenitor cell. Is neurotransmitter signaling the relevant target of the hits identified by the screen (as opposed to off-target effects)? On the one hand, there are some indications that neuro-modulatory pathways are involved, including chemical diversity within the active compound classes, which suggests that common off-target effects are unlikely, and inhibition of the antiproliferative effect of the D2/3 dopa-mine receptor agonist bromocriptine by coad-ministration of the D2 receptor antagonist (±)-sulpride. On the other hand, physiologic evidence for the suspected neurotransmitter signaling needs to be documented. Moreover, if neurotransmitters are involved, do they act directly on the stem cells (Fig. 1a) or on more differentiated cells, which, as compared to stem cells, are more likely to have functional receptors (Fig. 1b)? It has been postulated that developmental neurotransmitter function on immature cells, but not necessarily stem cells, is important for establishing proper connec-tivity in the brain 8 , and the neuromodula-tory compounds could be interfering with a developmental function of neurotransmitter signaling recapitulated in the neurosphere culture. These simple models, however, must be distinguished from more complex alternatives, including the possibility that an antiproliferative or death response might be initiated in response to aberrant signaling caused by inappropriate binding of the neu-romodulatory hits to cellular proteins. Some of these mechanistic issues could be addressed through the use of selective molecular genetic tools, which would corroborate the basic finding while potentially addressing whether cell-autonomous versus cell-non-autonomous function is involved. Caveats aside, it is intriguing to consider that neurotransmitter regulation of NSCs is a normal homeostatic process in the ventricular subependyma, where forebrain NSCs reside, and that this process might be required for the proper wiring of the fetal and adult brain 9. This model could have profound implications for current therapeutic application of drugs that modulate neurotransmitter function, and would causally link anti-Parkinsonian drugs to the recent finding of reduced prevalence of brain tumors in patients with Parkinson disease 10. Finally, the possibility that neu-rotransmitters are involved in cancer …