FAK deficiency in cells contributing to the basal lamina results in cortical abnormalities resembling congenital muscular dystrophies.
Targeted deletion of focal adhesion kinase (fak) in the developing dorsal forebrain resulted in local disruptions of the cortical basement membrane located between the neuroepithelium and pia-meninges. At disruption sites, clusters of neurons invaded the marginal zone. Retraction of radial glial endfeet, midline fusion of brain hemispheres, and gliosis also occurred, similar to type II cobblestone lissencephaly as seen in congenital muscular dystrophy. Interestingly, targeted deletion of fak in neurons alone did not result in cortical ectopias, indicating that fak deletion from glia is required for neuronal mislocalization. Unexpectedly, fak deletion specifically from meningeal fibroblasts elicited similar cortical ectopias in vivo and altered laminin organization in vitro. These observations provide compelling evidence that FAK plays a key signaling role in cortical basement membrane assembly and/or remodeling. In addition, FAK is required within neurons during development because neuron-specific fak deletion alters dendritic morphology in the absence of lamination defects.
Beggs
Hilary E
HE
Howard Hughes Medical Institute, Department of Physiology, University of California, San Francisco, CA 94143, USA. hbeggs@itsa.ucsf.edu
Schahin-Reed
Dorreyah
D
Zang
Keling
K
Goebbels
Sandra
S
Nave
Klaus Armin
KA
Gorski
Jessica
J
Jones
Kevin R
KR
Sretavan
David
D
Reichardt
Louis F
LF
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001426:Bacterial Proteins / Q000378:metabolism; D001485:Basement Membrane / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D064032:Calbindin 2; D064026:Calbindins; D002352:Carrier Proteins / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004388:Dura Mater; D049030:Dystroglycans; D004622:Embryo, Mammalian; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D007239:Infections; D047908:Intracellular Signaling Peptides and Proteins; D034882:Lamins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009136:Muscular Dystrophies / Q000151:congenital / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051857:Otx Transcription Factors; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000091042:Reelin Protein; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D012697:Serine Endopeptidases; D016622:Silver Staining; D013194:Staining and Labeling; D014157:Transcription Factors / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D001426:Bacterial Proteins; D064032:Calbindin 2; D064026:Calbindins; D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; D003598:Cytoskeletal Proteins; C483081:DAG1 protein, human; D004268:DNA-Binding Proteins; C490641:Etv1 protein, mouse; D016326:Extracellular Matrix Proteins; D005904:Glial Fibrillary Acidic Protein; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D034882:Lamins; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D051857:Otx Transcription Factors; D000091042:Reelin Protein; D064030:S100 Calcium Binding Protein G; D014157:Transcription Factors; D049030:Dystroglycans; C086961:PAB protein, Peptostreptococcus magnus; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; D019061:src-Family Kinases; D012697:Serine Endopeptidases; D010751:Phosphopyruvate Hydratase