Science Signaling最新文献_第3页

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-10-08 DOI: 10.1126/scisignal.adt5916

John F. Foley

引用次数: 0

A human DCC variant causing mirror movement disorder reveals that the WAVE regulatory complex mediates axon guidance by netrin-1–DCC 导致镜像运动障碍的人类 DCC 变异揭示了 WAVE 调节复合物通过净蛋白-1-DCC 介导轴突导向。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-10-01 DOI: 10.1126/scisignal.adk2345

Karina Chaudhari, Kaiyue Zhang, Patricia T. Yam, Yixin Zang, Daniel A. Kramer, Sarah Gagnon, Sabrina Schlienger, Sara Calabretta, Jean-Francois Michaud, Meagan Collins, Junmei Wang, Myriam Srour, Baoyu Chen, Frédéric Charron, Greg J. Bashaw

{"title":"A human DCC variant causing mirror movement disorder reveals that the WAVE regulatory complex mediates axon guidance by netrin-1–DCC","authors":"Karina Chaudhari, Kaiyue Zhang, Patricia T. Yam, Yixin Zang, Daniel A. Kramer, Sarah Gagnon, Sabrina Schlienger, Sara Calabretta, Jean-Francois Michaud, Meagan Collins, Junmei Wang, Myriam Srour, Baoyu Chen, Frédéric Charron, Greg J. Bashaw","doi":"10.1126/scisignal.adk2345","DOIUrl":"10.1126/scisignal.adk2345","url":null,"abstract":"<div >The axon guidance cue netrin-1 signals through its receptor DCC (deleted in colorectal cancer) to attract commissural axons to the midline. Variants in DCC are frequently associated with congenital mirror movements (CMMs). A CMM-associated variant in the cytoplasmic tail of DCC is located in a conserved motif predicted to bind to a regulator of actin dynamics called the WAVE (Wiskott-Aldrich syndrome protein–family verprolin homologous protein) regulatory complex (WRC). Here, we explored how this variant affects DCC function and may contribute to CMM. We found that a conserved WRC-interacting receptor sequence (WIRS) motif in the cytoplasmic tail of DCC mediated the interaction between DCC and the WRC. This interaction was required for netrin-1–mediated axon guidance in cultured rodent commissural neurons. Furthermore, the WIRS motif of Fra, the <i>Drosophila</i> DCC ortholog, was required for attractive signaling in vivo at the <i>Drosophila</i> midline. The CMM-associated R1343H variant of DCC, which altered the WIRS motif, prevented the DCC-WRC interaction and impaired axon guidance in cultured commissural neurons and in <i>Drosophila</i>. The findings reveal the WRC as a pivotal component of netrin-1–DCC signaling and uncover a molecular mechanism explaining how a human genetic variant in the cytoplasmic tail of DCC may lead to CMM.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 856","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The sex-dependent weight of autoimmunity 自身免疫的性别依赖性。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-10-01 DOI: 10.1126/scisignal.adt4125

Wei Wong

引用次数: 0

Amyloid-β oligomers trigger sex-dependent inhibition of GIRK channel activity in hippocampal neurons in mice 淀粉样β寡聚体会引发小鼠海马神经元 GIRK 通道活性的性别依赖性抑制。

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-10-01 DOI: 10.1126/scisignal.ado4132

Haichang Luo, Ezequiel Marron Fernandez de Velasco, Benjamin Gansemer, McKinzie Frederick, Carolina Aguado, Rafael Luján, Stanley A. Thayer, Kevin Wickman

{"title":"Amyloid-β oligomers trigger sex-dependent inhibition of GIRK channel activity in hippocampal neurons in mice","authors":"Haichang Luo, Ezequiel Marron Fernandez de Velasco, Benjamin Gansemer, McKinzie Frederick, Carolina Aguado, Rafael Luján, Stanley A. Thayer, Kevin Wickman","doi":"10.1126/scisignal.ado4132","DOIUrl":"10.1126/scisignal.ado4132","url":null,"abstract":"<div >Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by amyloid plaques and cognitive decline, the latter of which is thought to be driven by soluble oligomeric amyloid-β (oAβ). The dysregulation of G protein–gated inwardly rectifying K<sup>+</sup> (GIRK; also known as Kir3) channels has been implicated in rodent models of AD. Here, seeking mechanistic insights, we uncovered a sex-dependent facet of GIRK-dependent signaling in AD-related amyloid pathophysiology. Synthetic oAβ<sub>1–42</sub> suppressed GIRK-dependent signaling in hippocampal neurons from male mice, but not from female mice. This effect required cellular prion protein, the receptor mGluR5, and production of arachidonic acid by the phospholipase PLA<sub>2</sub>. Although oAβ suppressed GIRK channel activity only in male hippocampal neurons, intrahippocampal infusion of oAβ or genetic suppression of GIRK channel activity in hippocampal pyramidal neurons impaired performance on a memory test in both male and female mice. Moreover, genetic enhancement of GIRK channel activity in hippocampal pyramidal neurons blocked oAβ-induced cognitive impairment in both male and female mice. In APP/PS1 AD model mice, GIRK-dependent signaling was diminished in hippocampal CA1 pyramidal neurons from only male mice before cognitive deficit was detected. However, enhancing GIRK channel activity rescued cognitive deficits in older APP/PS1 mice of both sexes. Thus, whereas diminished GIRK channel activity contributes to cognitive deficits in male mice with increased oAβ burden, enhancing its activity may have therapeutic potential for both sexes.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 856","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Plaque to the future 通向未来的牌匾

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-09-24 DOI: 10.1126/scisignal.adt2301

Amy E. Baek

引用次数: 0

ProNGF elicits retrograde axonal degeneration of basal forebrain neurons through p75NTR and induction of amyloid precursor protein ProNGF 通过 p75NTR 和淀粉样前体蛋白诱导基底前脑神经元轴突逆行变性

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-09-24 DOI: 10.1126/scisignal.adn2616

Srestha Dasgupta, Mansi A. Pandya, Juan P. Zanin, Tong Liu, Qian Sun, Hong Li, Wilma J. Friedman

{"title":"ProNGF elicits retrograde axonal degeneration of basal forebrain neurons through p75NTR and induction of amyloid precursor protein","authors":"Srestha Dasgupta, Mansi A. Pandya, Juan P. Zanin, Tong Liu, Qian Sun, Hong Li, Wilma J. Friedman","doi":"10.1126/scisignal.adn2616","DOIUrl":"10.1126/scisignal.adn2616","url":null,"abstract":"<div >Basal forebrain cholinergic neurons (BFCNs) extend long projections to multiple regions in the brain to regulate cognitive functions. Degeneration of BFCNs is seen with aging, after brain injury, and in neurodegenerative disorders. An increase in the amount of the immature proform of nerve growth factor (proNGF) in the cerebral cortex results in retrograde degeneration of BFCNs through activation of proNGF receptor p75<sup>NTR</sup>. Here, we investigated the signaling cascades initiated at the axon terminal that mediate proNGF-induced retrograde degeneration. We found that local axonal protein synthesis and retrograde transport mediated proNGF-induced degeneration initiated from the axon terminal. Analysis of the nascent axonal proteome revealed that proNGF stimulation of axonal terminals triggered the synthesis of numerous proteins within the axon, and pathway analysis showed that amyloid precursor protein (APP) was a key upstream regulator in cultured BFCNs and in mice. Our findings reveal a functional role for APP in mediating BFCN axonal degeneration and cell death induced by proNGF.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 855","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A cholinergic signaling pathway underlying cortical circuit activation of quiescent neural stem cells in the lateral ventricle 激活侧脑室静止神经干细胞皮质回路的胆碱能信号通路

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-09-24 DOI: 10.1126/scisignal.adk8810

Moawiah M. Naffaa, Henry H. Yin

{"title":"A cholinergic signaling pathway underlying cortical circuit activation of quiescent neural stem cells in the lateral ventricle","authors":"Moawiah M. Naffaa, Henry H. Yin","doi":"10.1126/scisignal.adk8810","DOIUrl":"10.1126/scisignal.adk8810","url":null,"abstract":"<div >Neural stem cells (NSCs) in the subventricular zone (SVZ) located along the lateral ventricles (LVs) of the mammalian brain continue to self-renew to produce new neurons after birth and into adulthood. Quiescent LV cells, which are situated close to the ependymal cells lining the LVs, are activated by choline acetyltransferase–positive (ChAT<sup>+</sup>) neurons within the subependymal (subep) region of the SVZ when these neurons are stimulated by projections from the anterior cingulate cortex (ACC). Here, we uncovered a signaling pathway activated by the ACC-subep-ChAT<sup>+</sup> circuit responsible for the activation and proliferation of quiescent LV NSCs specifically in the ventral area of the SVZ. This circuit activated muscarinic M3 receptors on quiescent LV NSCs, which subsequently induced signaling mediated by the inositol 1,4,5-trisphosphate receptor type 1 (IP3R1). Downstream of IP3R1 activation, which would be expected to increase intracellular Ca<sup>2+</sup>, Ca<sup>2+</sup>-/calmodulin-dependent protein kinase II δ and the MAPK10 signaling pathway were stimulated and required for the proliferation of quiescent LV NSCs in the SVZ. These findings reveal the mechanisms that regulate quiescent LV NSCs and underscore the critical role of projections from the ACC in promoting their proliferative activity within the ventral SVZ.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 855","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DCLK1 induces a pro-tumorigenic phenotype to drive gastric cancer progression DCLK1 诱导促肿瘤表型，推动胃癌进展

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-09-17 DOI: 10.1126/scisignal.abq4888

Shoukat Afshar-Sterle, Annalisa L.E. Carli, Ryan O’Keefe, Janson Tse, Stefanie Fischer, Alexander I. Azimpour, David Baloyan, Lena Elias, Pathum Thilakasiri, Onisha Patel, Fleur M. Ferguson, Moritz F. Eissmann, Ashwini L. Chand, Nathanael S. Gray, Rita Busuttil, Alex Boussioutas, Isabelle S. Lucet, Matthias Ernst, Michael Buchert

{"title":"DCLK1 induces a pro-tumorigenic phenotype to drive gastric cancer progression","authors":"Shoukat Afshar-Sterle, Annalisa L.E. Carli, Ryan O’Keefe, Janson Tse, Stefanie Fischer, Alexander I. Azimpour, David Baloyan, Lena Elias, Pathum Thilakasiri, Onisha Patel, Fleur M. Ferguson, Moritz F. Eissmann, Ashwini L. Chand, Nathanael S. Gray, Rita Busuttil, Alex Boussioutas, Isabelle S. Lucet, Matthias Ernst, Michael Buchert","doi":"10.1126/scisignal.abq4888","DOIUrl":"10.1126/scisignal.abq4888","url":null,"abstract":"<div >Doublecortin-like kinase 1 (DCLK1) is a proposed driver of gastric cancer (GC) that phosphorylates serine and threonine residues. Here, we showed that the kinase activity of DCLK1 orchestrated cancer cell–intrinsic and–extrinsic processes that led to pro-invasive and pro-metastatic reprogramming of GC cells. Inhibition of the kinase activity of DCLK1 reduced the growth of subcutaneous xenograft tumors formed from MKN1 human gastric carcinoma cells in mice and decreased the abundance of the stromal markers α-Sma, vimentin, and collagen. Similar effects were seen in mice with xenograft tumors formed from MKN1 cells expressing a kinase-inactive DCLK1 mutant (MKN1<sup>D511N</sup>). MKN1<sup>D511N</sup> cells also had reduced in vitro migratory potential and stemness compared with control cells. Mice orthotopically grafted with MKN1 cells overexpressing DCLK1 (MKN1<sup>DCLK1</sup>) showed increased invasiveness and had a greater incidence of lung metastases compared with those grafted with control MKN1 cells. Mechanistically, we showed that the chemokine CXCL12 acted downstream of DCLK1 in cultured MKN1 cells and in mice subcutaneously implanted with gastric tumors formed by MKN1<sup>DCLK1</sup> cells. Moreover, inhibition of the kinase activity of DCLK1 or the expression of DCLK1<sup>D511N</sup> reversed the pro-tumorigenic and pro-metastatic phenotype. Together, this study establishes DCLK1 as a broadly acting and potentially targetable promoter of GC.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 854","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Suppressing appetite with taurine 用牛磺酸抑制食欲

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-09-17 DOI: 10.1126/scisignal.adt0770

Annalisa M. VanHook

引用次数: 0

The role of signaling pathways mediated by the GPCRs CysLTR1/2 in melanocyte proliferation and senescence GPCR CysLTR1/2 介导的信号通路在黑色素细胞增殖和衰老中的作用

IF 6.7 1区生物学

Science Signaling Pub Date : 2024-09-17 DOI: 10.1126/scisignal.adp3967

Thomas Huber, Mizuho Horioka-Duplix, Yuanhuang Chen, Victoria R. Saca, Emilie Ceraudo, Yu Chen, Thomas P. Sakmar

引用次数: 0