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1.
Front Cell Neurosci ; 13: 454, 2019.
Article in English | MEDLINE | ID: mdl-31749685

ABSTRACT

Corticothalamic axons express Contactin-2 (CNTN2/TAG-1), a neuronal recognition molecule of the immunoglobulin superfamily involved in neurogenesis, neurite outgrowth, and fasciculation. TAG-1, which is expressed transiently by cortical pyramidal neurons during embryonic development, has been shown to be fundamental for axonal recognition, cellular migration, and neuronal proliferation in the developing cortex. Although Tag-1 -/- mice do not exhibit any obvious defects in the corticofugal system, the role of TAG-1+ neurons during the development of the cortex remains elusive. We have generated a mouse model expressing EGFP under the Tag-1 promoter and encompassing the coding sequence of Diptheria Toxin subunit A (DTA) under quiescence with no effect on the expression of endogenous Tag-1. We show that while the line recapitulates the expression pattern of the molecule, it highlights an extended expression in the forebrain, including multiple axonal tracts and neuronal populations, both spatially and temporally. Crossing these mice to the Emx1-Cre strain, we ablated the vast majority of TAG-1+ cortical neurons. Among the observed defects were a significantly smaller cortex, a reduction of corticothalamic axons as well as callosal and commissural defects. Such defects are common in neurodevelopmental disorders, thus this mouse could serve as a useful model to study physiological and pathophysiological cortical development.

2.
J Cell Biol ; 216(11): 3785-3798, 2017 11 06.
Article in English | MEDLINE | ID: mdl-28912124

ABSTRACT

Cell spreading requires the coupling of actin-driven membrane protrusion and integrin-mediated adhesion to the extracellular matrix. The integrin-activating adaptor protein kindlin-2 plays a central role for cell adhesion and membrane protrusion by directly binding and recruiting paxillin to nascent adhesions. Here, we report that kindlin-2 has a dual role during initial cell spreading: it binds paxillin via the pleckstrin homology and F0 domains to activate Rac1, and it directly associates with the Arp2/3 complex to induce Rac1-mediated membrane protrusions. Consistently, abrogation of kindlin-2 binding to Arp2/3 impairs lamellipodia formation and cell spreading. Our findings identify kindlin-2 as a key protein that couples cell adhesion by activating integrins and the induction of membrane protrusions by activating Rac1 and supplying Rac1 with the Arp2/3 complex.


Subject(s)
Actin-Related Protein 2-3 Complex/metabolism , Cell Adhesion , Cell Shape , Cytoskeletal Proteins/metabolism , Fibroblasts/metabolism , Muscle Proteins/metabolism , Paxillin/metabolism , Pseudopodia/metabolism , Actin-Related Protein 2-3 Complex/genetics , Animals , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell Line , Cytoskeletal Proteins/deficiency , Cytoskeletal Proteins/genetics , Genotype , Mice, Knockout , Muscle Proteins/deficiency , Muscle Proteins/genetics , Neuropeptides/genetics , Neuropeptides/metabolism , Paxillin/genetics , Phenotype , Protein Binding , Protein Interaction Domains and Motifs , Signal Transduction , Talin/deficiency , Talin/genetics , rac1 GTP-Binding Protein/genetics , rac1 GTP-Binding Protein/metabolism
3.
Elife ; 5: e10130, 2016 Jan 27.
Article in English | MEDLINE | ID: mdl-26821125

ABSTRACT

Integrins require an activation step prior to ligand binding and signaling. How talin and kindlin contribute to these events in non-hematopoietic cells is poorly understood. Here we report that fibroblasts lacking either talin or kindlin failed to activate ß1 integrins, adhere to fibronectin (FN) or maintain their integrins in a high affinity conformation induced by Mn(2+). Despite compromised integrin activation and adhesion, Mn(2+) enabled talin- but not kindlin-deficient cells to initiate spreading on FN. This isotropic spreading was induced by the ability of kindlin to directly bind paxillin, which in turn bound focal adhesion kinase (FAK) resulting in FAK activation and the formation of lamellipodia. Our findings show that talin and kindlin cooperatively activate integrins leading to FN binding and adhesion, and that kindlin subsequently assembles an essential signaling node at newly formed adhesion sites in a talin-independent manner.


Subject(s)
Cell Adhesion , Cytoskeletal Proteins/metabolism , Fibroblasts/physiology , Integrin beta1/metabolism , Muscle Proteins/metabolism , Paxillin/metabolism , Talin/metabolism , Animals , Cell Line , Cell Movement , Fibroblasts/metabolism , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Manganese/metabolism , Mice , Protein Binding
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