Lgr4 Protein Deficiency Induces Ataxia-like Phenotype in Mice and Impairs Long Term Depression at Cerebellar Parallel Fiber-Purkinje Cell Synapses

Guan, Xin Yuan; Duan, Yi‐Shi; Zeng, Qingwen; Pan, Hongjie; Yu, Qing; Li, Dali; Cao, Xiaohua; Liu, Mingyao

doi:10.1074/jbc.m114.564138

Cited by 11 publications

(8 citation statements)

References 57 publications

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“…Lgr5 possesses b-arrestin recruitment motifs that are fully active under the appropriate conditions (Snyder et al, 2013a). Recent evidence demonstrates that the cerebellar Purkinje cells of hypomorphic Lgr4 mice have reduced levels of phospho-CREB, which can be restored through treatment with forskolin (Guan et al, 2014). This is further evidence that these receptors might couple to G proteins.…”

Section: Discussionmentioning

confidence: 64%

Lgr4 and Lgr5 drive the formation of long actin-rich cytoneme-like membrane protrusions

Snyder

Rochelle

Marion

et al. 2015

Journal of Cell Science

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Embryonic development and adult tissue homeostasis require precise information exchange between cells and their microenvironment to coordinate cell behavior. A specialized class of ultra-long actin-rich filopodia, termed cytonemes, provides one mechanism for this spatiotemporal regulation of extracellular cues. We provide here a mechanism whereby the stem-cell marker Lgr5, and its family member Lgr4, promote the formation of cytonemes. Lgr4-and Lgr5-induced cytonemes exceed lengths of 80 mm, are generated through stabilization of nascent filopodia from an underlying lamellipodial-like network and functionally provide a pipeline for the transit of signaling effectors. As proof-of-principle, we demonstrate that Lgr5-induced cytonemes act as conduits for cell signaling by demonstrating that the actin motor and filopodial cargo carrier protein myosin X (Myo10) and the G-protein-coupled receptor (GPCR) signaling effector b-arrestin-2 (Arrb2) transit into cytonemes. This work delineates a biological function for Lgr4 and Lgr5 and provides the rationale to fully investigate Lgr4 and Lgr5 function and cytonemes in mammalian stem cell and cancer stem cell behavior.

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Section: Discussionmentioning

confidence: 64%

Lgr4 and Lgr5 drive the formation of long actin-rich cytoneme-like membrane protrusions

Snyder

Rochelle

Marion

et al. 2015

Journal of Cell Science

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“…Lgr4 has been implicated in a broad array of biologic processes. Whole-body Lgr4 deletion is frequently embryonic lethal (55), with survivors bearing a host of developmental defects affecting bone (17,18,(56)(57)(58), blood (22,26), brain (13,59), eye (14,15,60), intestines (61,62), kidneys (63-65), bile duct (19), and reproductive organs (29,(66)(67)(68)(69)(70)(71). Several of these phenotypes were reported in humans bearing a nonsense mutation LGR4 allele (37).…”

Section: Discussionmentioning

confidence: 99%

LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells

Yue

Zeng

et al. 2017

FASEB j.

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The fourth member of the leucine-rich repeat-containing GPCR family (LGR4, frequently referred to as GPR48) and its cognate ligands, R-spondins (RSPOs) play crucial roles in the development of multiple organs as well as the survival of adult stem cells by activation of canonical Wnt signaling. Wnt/β-catenin signaling acts to regulate breast cancer; however, the molecular mechanisms determining its spatiotemporal regulation are largely unknown. In this study, we identified LGR4 as a master controller of Wnt/β-catenin signaling-mediated breast cancer tumorigenesis, metastasis, and cancer stem cell (CSC) maintenance. LGR4 expression in breast tumors correlated with poor prognosis. Either Lgr4 haploinsufficiency or mammary-specific deletion inhibited mouse mammary tumor virus (MMTV)- PyMT- and MMTV- Wnt1-driven mammary tumorigenesis and metastasis. Moreover, LGR4 down-regulation decreased in vitro migration and in vivo xenograft tumor growth and lung metastasis. Furthermore, Lgr4 deletion in MMTV- Wnt1 tumor cells or knockdown in human breast cancer cells decreased the number of functional CSCs by ∼90%. Canonical Wnt signaling was impaired in LGR4-deficient breast cancer cells, and LGR4 knockdown resulted in increased E-cadherin and decreased expression of N-cadherin and snail transcription factor -2 ( SNAI2) (also called SLUG), implicating LGR4 in regulation of epithelial-mesenchymal transition. Our findings support a crucial role of the Wnt signaling component LGR4 in breast cancer initiation, metastasis, and breast CSCs.-Yue, Z., Yuan, Z., Zeng, L., Wang, Y., Lai, L., Li, J., Sun, P., Xue, X., Qi, J., Yang, Z., Zheng, Y., Fang, Y., Li, D., Siwko, S., Li, Y., Luo, J., Liu, M. LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells.

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“…PCs, are the sole output neurons of the cerebellar cortex and are indispensable for the execution of its functions (Saywell et al, 2014 ). Defects in PC function can lead to cerebellar ataxia (Brown and Loew, 2012 ; Guan et al, 2014 ; Lucas et al, 2014 ) and behavioral abnormalities related to balance.…”

Section: Introductionmentioning

confidence: 99%

Toll-Like Receptor 4 Deficiency Impairs Motor Coordination

Zhu

Wang

et al. 2016

Front. Neurosci.

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The cerebellum plays an essential role in balance and motor coordination. Purkinje cells (PCs) are the sole output neurons of the cerebellar cortex and are critical for the execution of its functions, including motor coordination. Toll-like receptor (TLR) 4 is involved in the innate immune response and is abundantly expressed in the central nervous system; however, little is known about its role in cerebellum-related motor functions. To address this question, we evaluated motor behavior in TLR4 deficient mice. We found that TLR4−∕− mice showed impaired motor coordination. Morphological analyses revealed that TLR4 deficiency was associated with a reduction in the thickness of the molecular layer of the cerebellum. TLR4 was highly expressed in PCs but not in Bergmann glia or cerebellar granule cells; however, loss of TLR4 decreased the number of PCs. These findings suggest a novel role for TLR4 in cerebellum-related motor coordination through maintenance of the PC population.

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Lgr4 Protein Deficiency Induces Ataxia-like Phenotype in Mice and Impairs Long Term Depression at Cerebellar Parallel Fiber-Purkinje Cell Synapses

Cited by 11 publications

References 57 publications

Lgr4 and Lgr5 drive the formation of long actin-rich cytoneme-like membrane protrusions

Lgr4 and Lgr5 drive the formation of long actin-rich cytoneme-like membrane protrusions

LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells

Toll-Like Receptor 4 Deficiency Impairs Motor Coordination

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