Impact of Sim1 gene dosage on the development of the paraventricular and supraoptic nuclei of the hypothalamus.

The bHLH-PAS transcription SIM1 is required for the development of all neurons of the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus. Mice with a loss of Sim1 die within a few days of birth, presumably because of the lack of a PVN and SON. In contrast, mice with a decrease of Sim1 survive, are hyperphagic and become obese. The mechanism by which Sim1 controls food intake remains unclear. Here we show that the development of specific PVN and SON cell types is sensitive to Sim1 gene dosage. Sim1 haploinsufficiency reduces the number of vasopressin (AVP)- and oxytocin-producing cells in the PVN by about 50 and 80%, respectively, but does not affect the development of Crh, Trh and Ss neurons. A decrease of AVP-producing cells increases the sensitivity of Sim1 heterozygous mice to chronic dehydration. Moreover, retrograde labelling showed a 70% reduction of PVN neurons projecting to the dorsal vagal complex, raising the possibility that a decrease of these axons contributes to the hyperphagia of Sim1(+/-) mice. Sim1 haploinsufficiency is thus associated with a decrease of several PVN/SON cell types, which has the potential of affecting distinct homeostatic processes.

Looking for trouble: a search for developmental defects of the hypothalamus.

The hypothalamus is a critical integrator of several homeostatic processes that are required for the survival of vertebrates. Disruption of the development of the hypothalamus thus has the potential of perturbing important physiological processes with lifelong consequences. We review current knowledge about how cell types are specified and circuits are formed within the developing hypothalamus. We emphasize the potential clinical impact of the perturbations of these pathways using the regulation of energy balance as a model. We predict that disruption of hypothalamic development is a common, previously unsuspected cause of disorders of homeostatic processes such as obesity and high blood pressure.

Antitumor activity of fibroblast growth factors (FGFs) for medulloblastoma may correlate with FGF receptor expression and tumor variant.

Members of the fibroblast growth factor (FGF) family, which normally control cerebellar neuronal maturation, may represent more natural and less toxic tools with which to target medulloblastoma (MB), an embryonal brain tumor thought to arise from cerebellar neuronal precursors. In support of this, we found previously basic FGF/FGF-2 can inhibit MB progression by inducing neuronal-like differentiation, slowing the growth, and triggering apoptosis of a MB cell line we established from a histopathologically classic tumor (R. L. Kenigsberg et al., Am. J. Pathol., 151: 867-881, 1997). In the present study, the usefulness of this approach is additionally investigated. We report that of the five FGFs found in the developing cerebellum, only two, FGF-2 and FGF-9, possess antitumoral activity for MB. This activity is only noted for cell lines that originate from classic (UM-MB1 and SYR) rather than desmoplastic (HSJ) tumors. Whereas these FGFs inhibit proliferation of both classic cell lines, they only advance neuronal differentiation and induce apoptosis of one, UM-MB1. Consistent with these responses, after FGF treatment, levels of neurofilaments and the proapoptotic modulator Bax only increase in UM-MB1, whereas the cyclin-dependent kinase inhibitor p27/Kip1 (p27), which accumulates in cerebellar neuronal precursors before they exit the cell cycle, goes up in both UM-MB1 and SYR. Finally, although the histological variant of MB may help predict the sensitivity of MB to the FGFs, the selectivity, specificity, and type of response elicited may be dictated by, as evident by immunoprecipitation and Western blot analyses, the expression of certain FGF receptor types.