Lis1 dysfunction leads to traction force reduction and cytoskeletal disorganization during cell migration

Jheng, Guo Wei; Hur, Sung Sik; Chang, Chia Ming; Wu, Chun Chi; Cheng, Jia Shing; Lee, Hsiao-Hui; Chung, Bon Chu; Wang, Yang Kao; Lin, Keng Hui; Álamo, Juan C. del; Chien, Shu; Tsai, Jin Wu

doi:10.1016/j.bbrc.2018.02.151

Cited by 25 publications

(26 citation statements)

References 37 publications

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“…Our data show that the activation of PKA by the ciliary produced cAMP hotspot regulates the speed of migration via centrosome/nucleus coupling. A likely PKA downstream effector could be the LIS1-dynein-nde1-ndeL1 complex, which is localized at the centrosome (Sasaki et al, 2000;Tanaka et al, 2004), essential for neuronal migration in diverse types of neurons (Bradshaw et al, 2011;Shu et al, 2004;Tsai et al, 2007) and involved in centrosome/nucleus coupling (Jheng et al, 2018;Tsai et al, 2007). PKA phosphorylates Ndel1 and Nde1, which induces the release of LIS1 and dynein from the complex (Bradshaw et al, 2011;Tsai et al, 2007) thus allowing their action on microtubule stability (Hendricks et al, 2012;Sapir, 1997).…”

Section: Centrosomal Localization Of Pkamentioning

confidence: 99%

“…For each somal translocation, nucleus and centrosome move forward in a "two-stroke" cycle, with the centrosome moving first within a swelling in the leading process (centrokinesis, CK) and the nucleus following subsequently (nucleokinesis, NK) (Bellion et al, 2005;Belvindrah et al, 2017;Schaar and McConnell, 2005). Regulation of centrosome dynamics is thus pivotal in the regulation of migration, through microtubular nucleus to centrosome coupling allowing NK (Belvindrah et al, 2017;Jheng et al, 2018;Tanaka et al, 2004;Tsai et al, 2007) The centrosome is located at the basis of the primary cilium (PC), a small rod-shaped organelle important for migration. It is present on most eukaryotic cells including neurons (Mandl and Megele, 1989).…”

Section: Introductionmentioning

confidence: 99%

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Primary cilium-dependent cAMP/PKA signaling at the centrosome regulates neuronal migration

Stoufflet

Chaulet

Doulazmi

et al. 2019

Preprint

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The primary cilium (PC) is crucial for neuronal migration but the underlying cellular mechanisms are mostly unknown. Here, we show that ciliary-produced cAMP present at the centrosome locally activates cAMP-dependent Protein Kinase A (PKA). We analyzed cAMP dynamics through biosensor live-imaging in cyclic saltatory migrating neurons of the mouse postnatal rostral migratory stream. This revealed a dynamic cAMP hotspot cyclically present at the centrosome, thus located at the basis of the PC. Genetic ablation of the PC and knockdown of the ciliary Adenylate Cyclase 3 lead to the hotspot disappearance. They also affect migration with defective centrosome/nucleus coupling leading to altered nucleokinesis, which is recapitulated by PKA genetic delocalization. We thus show that PC and centrosome act as a single signaling unit, linked by ciliary cAMP diffusion regulating the rhythmicity of saltatory migration at the centrosome. We generalized this finding to embryonic and adult migrating neurons.

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Section: Centrosomal Localization Of Pkamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Primary cilium-dependent cAMP/PKA signaling at the centrosome regulates neuronal migration

Stoufflet

Chaulet

Doulazmi

et al. 2019

Preprint

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“…Indeed, Lis1 interacts with Rac1 and IQGAP [5], both of which localize to the phagocytic cup [31] [32]. Lis1 is involved in regulating extra-cellular adhesion complexes for cellcell [33] or cell-substratum adhesion during cell migration [6], where the cortical machinery mediates translocation of the cell membrane against a rigid substratum. In a similar fashion, phagocytosis also involves activity of the cortical machinery to deform the cell membrane and exert force on the phagocytosed particle to drive its inward movement [34].…”

Section: Discussionmentioning

confidence: 99%

“…However, outside this classical dynein-dependent pathway, Lis1 also acts as a scaffold for actinnucleating machinery at the leading edge of neuronal growth cones in the developing brain [5]. Lis1 also cross-talks with the extracellular adhesion complex at the focal adhesions of fibroblasts [6], and is necessary for generating forces against the substratum for cell migration. Knockdown of Lis1 reduces F-actin concentration at the leading edge of neurons [7].…”

Section: Introductionmentioning

confidence: 99%

Lis1 regulates Phagocytosis by co-localising with actin in the Phagocytic cup

Chhatre

Sanghavi

Mallik

2019

Preprint

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Phagocytosis, the ingestion of solid particles by cells, is essential for nutrient uptake, innate immune response, antigen presentation and organelle homeostasis. Here we show that Lissencephaly-1 (Lis1), a well-known regulator of the microtubule motor Dynein, also co-localises with actin at the phagocytic cup in the early stages of phagocytosis. Both knockdown and overexpression of Lis1 perturbs phagocytosis, suggesting that an optimum level of Lis1 is required to regulate actin dynamics within the phagocytic cup during particle engulfment. This requirement of Lis1 is replicated in mouse macrophage cells as well as in the amoeba Dictyostelium, indicating an evolutionarily conserved role for Lis1 in phagocytosis. In support of these findings, a general role for Lis1 in regulating actin dynamics is suggested by observing defective migration of cells overexpressing Lis1. Taken together, Lis1 localises to the phagocytic cup and influences actin dynamics in a manner that is important for the uptake of solid particles in cells.

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“…Human Lissencephaly-1 (LIS1) haploinsufficiency is the most common genetic cause of a neuronal migration disorder called lissencephaly (Dobyns et al, 1993;Hattori et al, 1994; Moon et al, 2013). LIS1 is a key regulator of cytoplasmic dynein and microtubules (MTs), and it has been proposed as an important molecular link coordinating both MTs and actin (Kholmanskiki 2003;Kholmanskiki 2006;Jheng et al, 2018). Besides an indispensible role for LIS1 in neuronal migration in post-mitotic neurons, Lis1 mutant mouse studies suggest pivotal roles of LIS1 in neocortical neural progenitor cell (NPC) division (Yingling et al, 2008;Youn et al, 2009;Hippenmeyer et al, 2010;Bershteyn et al, 2017) by regulating mitotic spindles (Yingling et al, 2008;Moon et al, 2014), consistent with other mutants of MT/dynein-associated proteins such as LGN, NDE1, and NDEL1 (Fuga et al, 2004;Bradshaw and Hayashi 2017;Doobin et al, 2016;Wynne et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

LIS1 determines cleavage plane positioning by regulating actomyosin-mediated cell membrane contractility

Moon

Hippenmeyer

Luo

et al. 2019

Preprint

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Heterozygous loss of human PAFAH1B1 (coding for LIS1) results in the disruption of neurogenesis and neuronal migration via dysregulation of microtubule (MT) stability and dynein motor function/localization that alters mitotic spindle orientation, chromosomal segregation, and nuclear migration. Recently, human induced pluripotent stem cell (iPSC) models revealed an important role for LIS1 in controlling the length of terminal cell divisions of outer radial glial (oRG) progenitors, suggesting cellular functions of LIS1 in regulating neural progenitor cell (NPC) daughter cell separation. Here we examined the late mitotic stages NPCs in vivo and mouse embryonic fibroblasts (MEFs) in vitro from Lis1-deficient mutants. Lis1-deficient neocortical NPCs and MEFs similarly exhibited cleavage plane displacement with mislocalization of furrow-associated markers, associated with actomyosin dysfunction and cell membrane hyper-contractility.Thus, it suggests LIS1 acts as a key molecular link connecting MTs/dynein and actomyosin, ensuring that cell membrane contractility is tightly controlled to execute proper daughter cell separation.

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Lis1 dysfunction leads to traction force reduction and cytoskeletal disorganization during cell migration

Cited by 25 publications

References 37 publications

Primary cilium-dependent cAMP/PKA signaling at the centrosome regulates neuronal migration

Primary cilium-dependent cAMP/PKA signaling at the centrosome regulates neuronal migration

Lis1 regulates Phagocytosis by co-localising with actin in the Phagocytic cup

LIS1 determines cleavage plane positioning by regulating actomyosin-mediated cell membrane contractility

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