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Development. 2015 Sep 1;142(17):3009-20. doi: 10.1242/dev.122176. Epub 2015 Aug 7.

Meis1 coordinates a network of genes implicated in eye development and microphthalmia.

Author information

1
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.
2
Departamento de Desarrollo y Reparación Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares (CNIC), c/Melchor Fernández Almagro, 3, Madrid E-28029, Spain.
3
Institute of Developmental Genetics Helmholtz Center Munich, Neuherberg D-85764, Germany.
4
Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares (CNIC), c/Melchor Fernández Almagro, 3, Madrid E-28029, Spain.
5
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.
6
Centro Andaluz de Biología del Desarrollo (CABD), CSIC-UPO, Carretera de Utrera Km1, Sevilla E-41013, Spain.
7
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.
8
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.

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.

KEYWORDS:

Developmental disorders; Microphthalmia; Mouse; Notch signaling; Patterning; TALE transcription factors

PMID:
26253404
DOI:
10.1242/dev.122176
[Indexed for MEDLINE]
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