SignificanceWhile knowledge of signaling mechanisms orchestrating the development and diversification of peripheral somatosensory neurons is extensive, our understanding of the mechanisms controlling chemosensory neuron specification remains rudimentary. Lingually projecting sensory neurons of the geniculate ganglion are receptive to the five taste qualities, as well as temperature and tactile stimuli, but the mechanisms responsible for the diversification of the unique subpopulations that respond to one, or several, of these stimuli remain unknown. Here we demonstrate that the GDNF-Ret signaling pathway exerts a unique, dual function in peripheral taste system development and postnatal function. Ret acts embryonically to regulate the expression of the chemosensory master regulator Phox2b, thus inducing chemosensory differentiation, while postnatally acting to specify a molecularly unique subpopulation of lingual mechanoreceptors.

Background-Most medullary thyroid carcinomas (MTC) recur or progress despite optimal surgical resection. Current targeted-therapies show promise but lack durable efficacy and tolerability. The purpose of this study was to build upon previous in vitro work and evaluate Withaferin A (WA), a novel RET inhibitor, in a metastatic murine model of MTC.

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Objective Deep vein thrombosis (VT) can result in vein wall injury, which clinically manifests as post thrombotic syndrome. Post injury fibrosis may be modulated in part through cellular cysteine-cysteine receptor 7 (CCR7) mediated events. We tested the hypothesis that late vein wall fibrotic remodeling is dependent on CCR7. Approach and Results CCR7−/− and C57BL/6 wild type (WT) mice had inferior vena cava VT induced by non-stasis or stasis mechanisms. In both models, VT size was largest at d1, and trended down by d21, while CCR7+ cells peaked at d8 in WT mice. No significant differences in VT resolution were found in CCR7−/− as compared with WT in either model. In the non-stasis VT model, vein wall changes consistent with fibrotic injury was evidenced by significant increases in collagen I, III, MMP2 and TGF-b gene expression, increases in αSMA and FSP-1 antigen, and total collagen at 8d. Correspondingly, SM22α and FSP-1, but not DDR2 positive cells were increased at 8d. Early WT thrombus exposure inhibited profibrotic gene expression in CCR7−/− in ex vivo vein wall culture. Bone marrow chimera experiments further showed circulating CCR7+ leukocytes partially rescued midterm profibrotic changes in CCR7−/− mice. In human histologic sections of chronic thrombosed femoral veins, CCR7+ cells were present in the fibrotic areas. Conclusions Post thrombotic vein wall remodeling is impaired in CCR7−/− mice, with a profibrotic phenotype, is dependent on the thrombotic mechanism, and is mediated by circulating CCR7+ cells. Unlike other post injury fibrotic responses, CCR7+ signaling may be important for positive vein wall remodeling after VT.

Accessory spleens can be readily detected at laparoscopy in the vicinity of the spleen; preoperative CT scan for their detection and localization may not be necessary.