title: Meis1 coordinates a network of genes implicated in eye development and microphthalmia.
abstract: Microphthalmos is a rare congenital anomaly characterized by reduced eye size and visual deficits of variable degree. Sporadic and hereditary microphthalmos have been associated with heterozygous mutations in genes fundamental for eye development. Yet, many cases are idiopathic or await the identification of molecular causes. Here we show that haploinsufficiency of Meis1, which encodes a transcription factor with evolutionarily conserved expression in the embryonic trunk, brain and sensory organs, including the eye, causes microphthalmic traits and visual impairment in adult mice. By combining analysis of Meis1 loss-of-function and conditional Meis1 functional rescue with ChIP-seq and RNA-seq approaches we show that, in contrast to its preferential association with Hox-Pbx BSs in the trunk, Meis1 binds to Hox/Pbx-independent sites during optic cup development. In the eye primordium, Meis1 coordinates, in a dose-dependent manner, retinal proliferation and differentiation by regulating genes responsible for human microphthalmia and components of the Notch signaling pathway. In addition, Meis1 is required for eye patterning by controlling a set of eye territory-specific transcription factors, so that in Meis1(-/-) embryos boundaries among the different eye territories are shifted or blurred. We propose that Meis1 is at the core of a genetic network implicated in eye patterning/microphthalmia, and represents an additional candidate for syndromic cases of these ocular malformations.
authors.affiliation: Centro de Biología Molecular "Severo Ochoa", CSIC-UAM, c/Nicolás Cabrera, 1, Madrid E-28049, Spain CIBER de Enfermedades Raras (CIBERER), c/Nicolás Cabrera, 1, Madrid E-28049, Spain.
authors.forename: Séverine
authors.initials: S
authors.lastname: Marcos
authors.affiliation: Departamento de Desarrollo y Reparación Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares (CNIC), c/Melchor Fernández Almagro, 3, Madrid E-28029, Spain.
authors.forename: Monica
authors.initials: M
authors.lastname: González-Lázaro
authors.affiliation: Centro de Biología Molecular "Severo Ochoa", CSIC-UAM, c/Nicolás Cabrera, 1, Madrid E-28049, Spain CIBER de Enfermedades Raras (CIBERER), c/Nicolás Cabrera, 1, Madrid E-28049, Spain.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Beccari
authors.affiliation: Departamento de Desarrollo y Reparación Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares (CNIC), c/Melchor Fernández Almagro, 3, Madrid E-28029, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Carramolino
authors.affiliation: Centro de Biología Molecular "Severo Ochoa", CSIC-UAM, c/Nicolás Cabrera, 1, Madrid E-28049, Spain CIBER de Enfermedades Raras (CIBERER), c/Nicolás Cabrera, 1, Madrid E-28049, Spain.
authors.forename: Maria Jesus
authors.initials: MJ
authors.lastname: Martin-Bermejo
authors.affiliation: Institute of Developmental Genetics Helmholtz Center Munich, Neuherberg D-85764, Germany.
authors.forename: Oana
authors.initials: O
authors.lastname: Amarie
authors.affiliation: Departamento de Desarrollo y Reparación Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares (CNIC), c/Melchor Fernández Almagro, 3, Madrid E-28029, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mateos-San Martín
authors.affiliation: Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares (CNIC), c/Melchor Fernández Almagro, 3, Madrid E-28029, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Torroja
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD), CSIC-UPO, Carretera de Utrera Km1, Sevilla E-41013, Spain ARC Center of Excellence in Plant Energy Biology, School of Chemistry and Biochemistry, Faculty of Science, The University of Western Australia, Perth, Western Australia 6009, Australia.
authors.forename: Ozren
authors.initials: O
authors.lastname: Bogdanović
authors.affiliation: Departamento de Desarrollo y Reparación Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares (CNIC), c/Melchor Fernández Almagro, 3, Madrid E-28029, Spain.
authors.forename: Roisin
authors.initials: R
authors.lastname: Doohan
authors.affiliation: Institute of Developmental Genetics Helmholtz Center Munich, Neuherberg D-85764, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Puk
authors.affiliation: Institute of Developmental Genetics Helmholtz Center Munich, Neuherberg D-85764, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě de Angelis
authors.affiliation: Institute of Developmental Genetics Helmholtz Center Munich, Neuherberg D-85764, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Graw
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD), CSIC-UPO, Carretera de Utrera Km1, Sevilla E-41013, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Gomez-Skarmeta
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD), CSIC-UPO, Carretera de Utrera Km1, Sevilla E-41013, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Casares
authors.affiliation: Departamento de Desarrollo y Reparación Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares (CNIC), c/Melchor Fernández Almagro, 3, Madrid E-28029, Spain mtorres@cnic.es pbovolenta@cbm.csic.es.
authors.forename: Miguel
authors.initials: M
authors.lastname: Torres
authors.affiliation: Centro de Biología Molecular "Severo Ochoa", CSIC-UAM, c/Nicolás Cabrera, 1, Madrid E-28049, Spain CIBER de Enfermedades Raras (CIBERER), c/Nicolás Cabrera, 1, Madrid E-28049, Spain mtorres@cnic.es pbovolenta@cbm.csic.es.
authors.forename: Paola
authors.initials: P
authors.lastname: Bovolenta
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005123:Eye / Q000196:embryology* / Q000378:metabolism*; D053263:Gene Regulatory Networks; D057895:Haploinsufficiency / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008850:Microphthalmos / Q000196:embryology* / Q000235:genetics*; D008969:Molecular Sequence Data; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics; D011485:Protein Binding; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D051880:Receptors, Notch
keywords: Developmental disorders; Microphthalmia; Mouse; Notch signaling; Patterning; TALE transcription factors