title: Crim1 regulates integrin signaling in murine lens development.
abstract: The developing lens is a powerful system for investigating the molecular basis of inductive tissue interactions and for studying cataract, the leading cause of blindness. The formation of tightly controlled cell-cell adhesions and cell-matrix junctions between lens epithelial (LE) cells, between lens fiber (LF) cells, and between these two cell populations enables the vertebrate lens to adopt a highly ordered structure and acquire optical transparency. Adhesion molecules are thought to maintain this ordered structure, but little is known about their identity or interactions. Cysteine-rich motor neuron 1 (Crim1), a type I transmembrane protein, is strongly expressed in the developing lens and its mutation causes ocular disease in both mice and humans. How Crim1 regulates lens morphogenesis is not understood. We identified a novel ENU-induced hypomorphic allele of Crim1, Crim1(glcr11), which in the homozygous state causes cataract and microphthalmia. Using this and two other mutant alleles, Crim1(null) and Crim1(cko), we show that the lens defects in Crim1 mouse mutants originate from defective LE cell polarity, proliferation and cell adhesion. Crim1 adhesive function is likely to be required for interactions both between LE cells and between LE and LF cells. We show that Crim1 acts in LE cells, where it colocalizes with and regulates the levels of active β1 integrin and of phosphorylated FAK and ERK. The RGD and transmembrane motifs of Crim1 are required for regulating FAK phosphorylation. These results identify an important function for Crim1 in the regulation of integrin- and FAK-mediated LE cell adhesion during lens development.
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Jieqing
authors.initials: J
authors.lastname: Fan
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA Victor Chang Cardiac Research Institute, and The University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Joshua W K
authors.initials: JW
authors.lastname: Ho
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Tommy
authors.initials: T
authors.lastname: Hu
authors.affiliation: Howard Hughes Medical Institute and The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Kneeland
authors.affiliation: Renal Section, Department of Medicine, Boston University Medical Center, Boston, MA 02118, USA.
authors.forename: Xueping
authors.initials: X
authors.lastname: Fan
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Qiongchao
authors.initials: Q
authors.lastname: Xi
authors.affiliation: Victor Chang Cardiac Research Institute, and The University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Sellarole
authors.affiliation: Victor Chang Cardiac Research Institute, and The University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Wilhelmine N
authors.initials: WN
authors.lastname: de Vries
authors.affiliation: Renal Section, Department of Medicine, Boston University Medical Center, Boston, MA 02118, USA.
authors.forename: Weining
authors.initials: W
authors.lastname: Lu
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA.
authors.forename: Salil A
authors.initials: SA
authors.lastname: Lachke
authors.affiliation: Department of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lang
authors.affiliation: Victor Chang Cardiac Research Institute, and The University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Simon W M
authors.initials: SW
authors.lastname: John
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA maas@genetics.med.harvard.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Maas
mesh_terms: D000818:Animals; D052004:Bone Morphogenetic Protein Receptors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007908:Lens, Crystalline / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D038081:Organogenesis / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology
chemical_list: C518411:Crim1 protein, mouse; D052004:Bone Morphogenetic Protein Receptors
keywords: Cataract; Cell adhesion; Crim1; Cysteine-rich transmembrane BMP regulator 1; Eye development; Integrin; Lens; Mouse