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Li Lab / Publications
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25 Publications

Showing 21-25 of 25 results
06/28/16 | Transmembrane channel-like (tmc) gene regulates Drosophila larval locomotion.
Guo Y, Wang Y, Zhang W, Meltzer S, Zanini D, Yu Y, Li J, Cheng T, Guo Z, Wang Q, Jacobs JS, Sharma Y, Eberl DF, Göpfert MC, Jan LY, Jan YN, Wang Z
Proc Natl Acad Sci U S A. 06/2016;113(26):7243-8. doi: 10.1073/pnas.1606537113

Drosophila larval locomotion, which entails rhythmic body contractions, is controlled by sensory feedback from proprioceptors. The molecular mechanisms mediating this feedback are little understood. By using genetic knock-in and immunostaining, we found that the Drosophila melanogaster transmembrane channel-like (tmc) gene is expressed in the larval class I and class II dendritic arborization (da) neurons and bipolar dendrite (bd) neurons, both of which are known to provide sensory feedback for larval locomotion. Larvae with knockdown or loss of tmc function displayed reduced crawling speeds, increased head cast frequencies, and enhanced backward locomotion. Expressing Drosophila TMC or mammalian TMC1 and/or TMC2 in the tmc-positive neurons rescued these mutant phenotypes. Bending of the larval body activated the tmc-positive neurons, and in tmc mutants this bending response was impaired. This implicates TMC's roles in Drosophila proprioception and the sensory control of larval locomotion. It also provides evidence for a functional conservation between Drosophila and mammalian TMCs.

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09/10/15 | Ankyrin Repeats Convey Force to Gate the NOMPC Mechanotransduction Channel.
Zhang W, Cheng LE, Kittelmann M, Li J, Petkovic M, Cheng T, Jin P, Guo Z, Göpfert MC, Jan LY, Jan YN
Cell. 09/2015;162(6):1391-403. doi: 10.1016/j.cell.2015.08.024

How metazoan mechanotransduction channels sense mechanical stimuli is not well understood. The NOMPC channel in the transient receptor potential (TRP) family, a mechanotransduction channel for Drosophila touch sensation and hearing, contains 29 Ankyrin repeats (ARs) that associate with microtubules. These ARs have been postulated to act as a tether that conveys force to the channel. Here, we report that these N-terminal ARs form a cytoplasmic domain essential for NOMPC mechanogating in vitro, mechanosensitivity of touch receptor neurons in vivo, and touch-induced behaviors of Drosophila larvae. Duplicating the ARs elongates the filaments that tether NOMPC to microtubules in mechanosensory neurons. Moreover, microtubule association is required for NOMPC mechanogating. Importantly, transferring the NOMPC ARs to mechanoinsensitive voltage-gated potassium channels confers mechanosensitivity to the chimeric channels. These experiments strongly support a tether mechanism of mechanogating for the NOMPC channel, providing insights into the basis of mechanosensitivity of mechanotransduction channels.

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06/01/15 | A transcriptional reporter of intracellular Ca(2+) in Drosophila.
Gao XJ, Riabinina O, Li J, Potter CJ, Clandinin TR, Luo L
Nat Neurosci. 06/2015;18(6):917-25. doi: 10.1038/nn.4016

Intracellular Ca(2+) is a widely used neuronal activity indicator. Here we describe a transcriptional reporter of intracellular Ca(2+) (TRIC) in Drosophila that uses a binary expression system to report Ca(2+)-dependent interactions between calmodulin and its target peptide. We found that in vitro assays predicted in vivo properties of TRIC and that TRIC signals in sensory systems depend on neuronal activity. TRIC was able to quantitatively monitor neuronal responses that changed slowly, such as those of neuropeptide F-expressing neurons to sexual deprivation and neuroendocrine pars intercerebralis cells to food and arousal. Furthermore, TRIC-induced expression of a neuronal silencer in nutrient-activated cells enhanced stress resistance, providing a proof of principle that TRIC can be used for circuit manipulation. Thus, TRIC facilitates the monitoring and manipulation of neuronal activity, especially those reflecting slow changes in physiological states that are poorly captured by existing methods. TRIC's modular design should enable optimization and adaptation to other organisms.

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01/01/15 | NAD⁺/NADH metabolism and NAD⁺-dependent enzymes in cell death and ischemic brain injury: current advances and therapeutic implications.
Ma Y, Nie H, Chen H, Li J, Hong Y, Wang B, Wang C, Zhang J, Cao W, Zhang M, Xu Y, Ding X, Yin SK, Qu X, Ying W
Curr Med Chem. 2015;22(10):1239-47. doi: 10.2174/0929867322666150209154420

NAD(+) and NADH play crucial roles in a variety of biological processes including energy metabolism, mitochondrial functions, and gene expression. Multiple studies have indicated that NAD(+) administration can profoundly decrease oxidative cell death as well as ischemic and traumatic brain injury, suggesting NAD(+) metabolism as a promising therapeutic target for cerebral ischemia and head injury. Cumulating evidence has suggested that NAD(+) can produce its protective effects by multiple mechanisms, including preventing mitochondrial alterations, enhancing energy metabolism, preventing virtually all forms of cell death including apoptosis, necrosis and autophagy, inhibiting inflammation, directly increasing antioxidation capacity of cells and tissues, and activating SIRT1. Increasing evidence has also suggested that NADH metabolism is a potential therapeutic target for treating several neurological disorders. A number of studies have further indicated that multiple NAD(+)-dependent enzymes such as sirtuins, polymerase(ADP-ribose) polymerases (PARPs) and CD38 mediate cell death and multiple biological processes. In this article, an overview of the recent findings regarding the roles of NAD(+)/NADH and NAD(+)-dependent enzymes in cell death and ischemic brain injury is provided. These findings have collectively indicated that NAD(+)/NADH and NAD(+)-dependent enzymes play fundamental roles in oxidative stress-induced cell death and ischemic brain injury, which may become promising therapeutic targets for brain ischemia and multiple other neurological disorders.

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08/05/14 | Cytoplasmic tyrosine phosphatase Shp2 coordinates hepatic regulation of bile acid and FGF15/19 signaling to repress bile acid synthesis.
Li S, Hsu DD, Li B, Luo X, Alderson N, Qiao L, Ma L, Zhu HH, He Z, Suino-Powell K, Ji K, Li J, Shao J, Xu HE, Li T, Feng G
Cell Metab. 08/2014;20(2):320-32. doi: 10.1016/j.cmet.2014.05.020

Bile acid (BA) biosynthesis is tightly controlled by intrahepatic negative feedback signaling elicited by BA binding to farnesoid X receptor (FXR) and also by enterohepatic communication involving ileal BA reabsorption and FGF15/19 secretion. However, how these pathways are coordinated is poorly understood. We show here that nonreceptor tyrosine phosphatase Shp2 is a critical player that couples and regulates the intrahepatic and enterohepatic signals for repression of BA synthesis. Ablating Shp2 in hepatocytes suppressed signal relay from FGFR4, receptor for FGF15/19, and attenuated BA activation of FXR signaling, resulting in elevation of systemic BA levels and chronic hepatobiliary disorders in mice. Acting immediately downstream of FGFR4, Shp2 associates with FRS2α and promotes the receptor activation and signal relay to several pathways. These results elucidate a molecular mechanism for the control of BA homeostasis by Shp2 through the orchestration of multiple signals in hepatocytes.

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