RESUMEN
Nervous systems are comprised of diverse cell types that differ functionally and morphologically. During development, extrinsic signals, e.g., growth factors, can activate intrinsic programs, usually orchestrated by networks of transcription factors. Within that network, transcription factors that drive the specification of features specific to a limited number of cells are often referred to as terminal selectors. While we still have an incomplete view of how individual neurons within organisms become specified, reporters limited to a subset of neurons in a nervous system can facilitate the discovery of cell specification programs. We have identified a fluorescent reporter that labels VD13, the most posterior of the 19 inhibitory GABA (γ-amino butyric acid)-ergic motorneurons, and two additional neurons, LUAL and LUAR. Loss of function in multiple Wnt signaling genes resulted in an incompletely penetrant loss of the marker, selectively in VD13, but not the LUAs, even though other aspects of GABAergic specification in VD13 were normal. The posterior Hox gene, egl-5, was necessary for expression of our marker in VD13, and ectopic expression of egl-5 in more anterior GABAergic neurons induced expression of the marker. These results suggest egl-5 is a terminal selector of VD13, subsequent to GABAergic specification.
RESUMEN
Pain is significantly impacted by the increasing epidemic of obesity and the metabolic syndrome. Our understanding of how these features impact pain is only beginning to be developed. Herein, we have investigated how small genetic differences among C57BL/6 mice from 2 different commercial vendors lead to important differences in the development of high-fat diet-induced mechanical sensitivity. Two substrains of C57BL/6 mice from Jackson Laboratories (Bar Harbor, ME; C57BL/6J and C57BL/6NIH), as well as C57BL/6 from Charles Rivers Laboratories (Wilmington, MA; C57BL/6CR) were placed on high-fat diets and analyzed for changes in metabolic features influenced by high-fat diet and obesity, as well as measures of pain-related behaviors. All 3 substrains responded to the high-fat diet; however, C57BL/6CR mice had the highest weights, fat mass, and impaired glucose tolerance of the 3 substrains. In addition, the C57BL/6CR mice were the only strain to develop significant mechanical sensitivity over the course of 8 weeks. Importantly, the C57BL/6J mice were protected from mechanical sensitivity, which may be based on increased physical activity compared with the other 2 substrains. These findings suggest that activity may play a powerful role in protecting metabolic changes associated with a high-fat diet and that these may also be protective in pain-associated changes as a result of a high-fat diet. These findings also emphasize the importance of selection and transparency in choosing C57BL/6 substrains in pain-related research. PERSPECTIVE: Obesity and the metabolic syndrome play an important role in pain. This study identifies key differences in the response to a high-fat diet among substrains of C57BL/6 mice and differences in intrinsic physical activity that may influence pain sensitivity. The results emphasize physical activity as a powerful modulator of obesity-related pain sensitivity.
