title: RASGRF2 controls nuclear migration in postnatal retinal cone photoreceptors.
abstract: Detailed immunocytochemical analyses comparing wild-type (WT), GRF1-knockout (KO), GRF2-KO and GRF1/2 double-knockout (DKO) mouse retinas uncovered the specific accumulation of misplaced, 'ectopic' cone photoreceptor nuclei in the photoreceptor segment (PS) area of retinas from GRF2-KO and GRF1/2-DKO, but not of WT or GRF1-KO mice. Localization of ectopic nuclei in the PS area of GRF2-depleted retinas occurred postnatally and peaked between postnatal day (P)11 and P15. Mechanistically, the generation of this phenotype involved disruption of the outer limiting membrane and intrusion into the PS layer by cone nuclei displaying significant perinuclear accumulation of signaling molecules known to participate in nuclear migration and cytoskeletal reorganization, such as PAR3, PAR6 and activated, phosphorylated forms of PAK, MLC2 and VASP. Electroretinographic recordings showed specific impairment of cone-mediated retinal function in GRF2-KO and GRF1/2-DKO retinas compared with WT controls. These data identify defective cone nuclear migration as a novel phenotype in mouse retinas lacking GRF2 and support a crucial role of GRF2 in control of the nuclear migration processes required for proper postnatal development and function of retinal cone photoreceptors.
authors.affiliation: Centro de Investigación del Cáncer-Instituto de Biología Molecular y Celular del Cáncer (CSIC - Universidad de Salamanca), Salamanca 37007, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Jimeno
authors.affiliation: Centro de Investigación del Cáncer-Instituto de Biología Molecular y Celular del Cáncer (CSIC - Universidad de Salamanca), Salamanca 37007, Spain.
authors.forename: Carmela
authors.initials: C
authors.lastname: Gómez
authors.affiliation: Centro de Investigación del Cáncer-Instituto de Biología Molecular y Celular del Cáncer (CSIC - Universidad de Salamanca), Salamanca 37007, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Calzada
authors.affiliation: Departamento de Fisiología, Universidad Alcalá, Alcalá de Henares 28871, Spain, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: de la Villa
authors.affiliation: INCYL, IBSAL (Universidad de Salamanca), Salamanca 37006, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Lillo
authors.affiliation: Centro de Investigación del Cáncer-Instituto de Biología Molecular y Celular del Cáncer (CSIC - Universidad de Salamanca), Salamanca 37007, Spain esantos@usal.es.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Santos
mesh_terms: D000818:Animals; D001692:Biological Transport; D002467:Cell Nucleus / Q000502:physiology*; D004596:Electroretinography; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012160:Retina / Q000166:cytology / Q000502:physiology; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000648:ultrastructure*; D015398:Signal Transduction; D020663:ras Guanine Nucleotide Exchange Factors / Q000502:physiology*
chemical_list: C504491:Rasgrf2 protein, mouse; D020663:ras Guanine Nucleotide Exchange Factors
keywords: Cone photoreceptor; GEF; GRF1; GRF2; Intracellular traffic; Nuclear migration; Ras signaling; Retina