| Summary: | Tubby mice succumb to blindness, deafness, and obesity. Vision and auditory deficits are attributed to neurodegeneration and tubby-associated obesity has been postulated to result from neuronal deficits in brain regions controlling weight regulation. TUB has been implicated in Gq signaling and 2 isoforms of TUB, found exclusively in the brain, may have opposing effects on transactivation. Toward this end, I developed several cell culture assays to interrogate TUB function and found that TUB directs neuronal outgrowth in an isoform-specific manner. One isoform directs stable and polar outgrowth while the other directs multiple process outgrowths and branching. These effects can occur via Gq signaling and require nuclear localization. Furthermore, I have found that the serotonergic system of tubby mice displays morphological and innervation deficits. Since the serotonergic system is implicated in modulating moods and behaviours, including appetite, these deficits may result in the obesity and motivational issues observed in tubby mice.
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