Leptin’s effects are mediated by interactions with a receptor that is alternatively spliced, resulting in at least five different murine forms: Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd, and Ob-Re. A mutation in one splice form, Ob-Rb, results in obesity in mice. Northern blots, RNase protection assays, and PCR indicate that Ob-Rb is expressed at a relatively high level in hypothalamus and low level in several other tissues. Ob-Ra is expressed ubiquitously, whereas Ob-Rc, -Rd, and -Re RNAs are only detectable using PCR. In hypothalamus, Ob-Rb is present in the arcuate, ventromedial, dorsomedial, and lateral hypothalamic nuclei but is not detectable in other brain regions. These nuclei are known to regulate food intake and body weight. The level of Ob-Rb in hypothalamus is reduced in mice rendered obese by gold thioglucose (GTG), which causes hypothalamic lesions. The obesity in GTG-treated mice is likely to be caused by ablation of Ob-Rb-expressing neurons, which results in leptin resistance.

The Hu proteins are a group of antigens targeted in an immune-mediated neurodegenerative disorder associated with cancer. We have cloned and characterized four members of theHugene family from mouse. We find that theHugenes encode a large number of alternatively spliced transcripts to produce a series of related neuron-specific RNA binding proteins. Despite this complexity, we have discerned several ordered features ofHuexpression. In the embryo, specificHugenes are expressed in a hierarchy during early neurogenesis. In the E16 developing cortex,mHuBis induced in very early postmitotic neurons exiting the ventricular zone,mHuDis expressed in migrating neurons of the intermediate zone, andmHuCis expressed in mature cortical plate neurons. Such a hierarchy suggests distinct functional roles for each gene in developing neurons. In the adult, all neurons express some set ofHumRNA and protein. However, specific patterns are evident such that individual neuronal types in the hippocampus, cerebellum, olfactory cortex, neocortex, and elsewhere express from one to severalHugenes. The complexity of potential protein variants within a gene family and of differentHufamily members within a neuron suggests a diverse array of function. Given the strong homologies among the Hu proteins, theDrosophilaneurogenic geneelav, and theDrosophilasplicing factorsxl, we predict that different combinations of Hu proteins determine different neuron-specific aspects of post-transcriptional RNA regulation. Our findings of specific developmental patterns of expression and the correlation between immune targeting of the Hu proteins and adult neurodegenerative disease suggest that the Hu proteins are critical in both the proper development and function of mature neurons.