title: Increased neuronal death and disturbed axonal growth in the Polμ-deficient mouse embryonic retina.
abstract: Programmed cell death occurs naturally at different stages of neural development, including neurogenesis. The functional role of this early phase of neural cell death, which affects recently differentiated neurons among other cell types, remains undefined. Some mouse models defective in DNA double-strand break (DSB) repair present massive cell death during neural development, occasionally provoking embryonic lethality, while other organs and tissues remain unaffected. This suggests that DSBs occur frequently and selectively in the developing nervous system. We analyzed the embryonic retina of a mouse model deficient in the error-prone DNA polymerase μ (Polμ), a key component of the non-homologous end-joining (NHEJ) repair system. DNA DSBs were increased in the mutant mouse at embryonic day 13.5 (E13.5), as well as the incidence of cell death that affected young neurons, including retinal ganglion cells (RGCs). Polμ(-/-) mice also showed disturbed RGC axonal growth and navigation, and altered distribution of the axonal guidance molecules L1-CAM and Bravo (also known as Nr-CAM). These findings demonstrate that Polμ is necessary for proper retinal development, and support that the generation of DSBs and their repair via the NHEJ pathway are genuine processes involved in neural development.
authors.affiliation: 3D Lab (Development, Differentiation and Degeneration), Centro de Investigaciones Biológicas, CSIC, 28040 Madrid, Spain.
authors.forename: Jimena
authors.initials: J
authors.lastname: Baleriola
authors.affiliation: 3D Lab (Development, Differentiation and Degeneration), Centro de Investigaciones Biológicas, CSIC, 28040 Madrid, Spain.
authors.forename: Noemí
authors.initials: N
authors.lastname: Álvarez-Lindo
authors.affiliation: System Biology Department, School of Medicine, Universidad de Alcalá, 28802 Alcalá de Henares, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: de la Villa
authors.affiliation: Centro Nacional de Biotecnología, CSIC, 28049 Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bernad
authors.affiliation: Centro de Biología Molecular Severo Ochoa, CSIC-UAM, 28049 Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Blanco
authors.affiliation: 3D Lab (Development, Differentiation and Degeneration), Centro de Investigaciones Biológicas, CSIC, 28040 Madrid, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Suárez
authors.affiliation: 3D Lab (Development, Differentiation and Degeneration), Centro de Investigaciones Biológicas, CSIC, 28040 Madrid, Spain.
authors.forename: Enrique J
authors.initials: EJ
authors.lastname: de la Rosa
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004259:DNA-Directed DNA Polymerase / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008954:Models, Biological; D055495:Neurogenesis; D012160:Retina / Q000166:cytology / Q000196:embryology* / Q000201:enzymology; D012165:Retinal Ganglion Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; C491151:Nrcam protein, mouse; C407743:DNA polymerase mu; D004259:DNA-Directed DNA Polymerase; C000626770:Polm protein, mouse