Male embryonic mice with mutations in the X-linked aristaless-related homeobox gene (Arx) developed with small brains due to suppressed proliferation and regional deficiencies in the forebrain. These mice also showed aberrant migration and differentiation of interneurons containing gamma-aminobutyric acid (GABAergic interneurons) in the ganglionic eminence and neocortex as well as abnormal testicular differentiation. These characteristics recapitulate some of the clinical features of X-linked lissencephaly with abnormal genitalia (XLAG) in humans. We found multiple loss-of-function mutations in ARX in individuals affected with XLAG and in some female relatives, and conclude that mutation of ARX causes XLAG. The present report is, to our knowledge, the first to use phenotypic analysis of a knockout mouse to identify a gene associated with an X-linked human brain malformation.

Leptin acts as a potent inhibitory factor against obesity by regulating energy expenditure, food intake, and adiposity. The obese diabetic db͞db mouse, which has defects in leptin receptor, displays enhanced neural responses and elevated behavioral preference to sweet stimuli. Here, we show the effects of leptin on the peripheral taste system. An administration of leptin into lean mice suppressed responses of peripheral taste nerves (chorda tympani and glossopharyngeal) to sweet substances (sucrose and saccharin) without affecting responses to sour, salty, and bitter substances. Whole-cell patch-clamp recordings of activities of taste receptor cells isolated from circumvallate papillae (innervated by the glossopharyngeal nerve) demonstrated that leptin activated outward K ؉ currents, which resulted in hyperpolarization of taste cells. The db͞db mouse with impaired leptin receptors showed no such leptin suppression. Taste tissue (circumvallate papilla) of lean mice expressed leptin-receptor mRNA and some of the taste cells exhibited immunoreactivities to antibodies of the leptin receptor. Taken together, these observations suggest that the taste organ is a peripheral target for leptin, and that leptin may be a sweet-sensing modulator (suppressor) that may take part in regulation of food intake. Defects in this leptin suppression system in db͞db mice may lead to their enhanced peripheral neural responses and enhanced behavioral preferences for sweet substances. Sweet-sensing taste receptor cells are very important for animals to be able to detect carbohydrate sources of calories. Previous studies demonstrated that genetically diabetic db͞db mice that exhibit extreme obesity (1, 2) have greater gustatory neural sensitivities (3-5) and higher behavioral preferences for various sweet substances (3) compared with lean control mice. In contrast, these mouse lines did not differ from controls in response to salty, sour, and bitter substances (NaCl, HCl, and quinine). The increase in sweet sensitivity as well as pancreatic ␤ cell activity (6) in db͞db mice has been reported to begin as early as 7 days of age, suggesting that these characteristics may be genetically induced by the action of the db locus. Recently, the ob gene has been cloned and found to encode the protein leptin (7). Leptin, released from adipocytes, has been found to inhibit food intake and to increase energy expenditure (8-11). Soon after these findings, it was revealed that the db gene encodes the leptin receptor (Ob-R) and that the db͞db mouse mutation occurs at the intracellular domain of the Ob-R (12-15), especially the signal-transducing long form of the Ob-R (Ob-Rb). This finding, therefore, raises the possibility that the enhanced sweet sensitivity of taste nerve responses in db͞db mice may be a consequence of defects in the Ob-Rb.In the present study, we investigated taste responses of receptor cells and peripheral nerves before and after leptin application. We demonstrate that the taste organ is a new peripheral target for leptin, that the Ob-...