RESUMO
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.
Assuntos
Olho/embriologia , Olho/metabolismo , Redes Reguladoras de Genes , Proteínas de Homeodomínio/metabolismo , Microftalmia/embriologia , Microftalmia/genética , Proteínas de Neoplasias/metabolismo , Envelhecimento/patologia , Animais , Apoptose/genética , Sequência de Bases , Sítios de Ligação , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Imunoprecipitação da Cromatina , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Elementos Facilitadores Genéticos/genética , Haploinsuficiência/genética , Hematopoese/genética , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Dados de Sequência Molecular , Proteína Meis1 , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/genética , Neurogênese/genética , Ligação Proteica , Receptores Notch/metabolismo , Transdução de Sinais/genéticaRESUMO
The interactions of Meis, Prep, and Pbx1 TALE homeoproteins with Hox proteins are essential for development and disease. Although Meis and Prep behave similarly in vitro, their in vivo activities remain largely unexplored. We show that Prep and Meis interact with largely independent sets of genomic sites and select different DNA-binding sequences, Prep associating mostly with promoters and housekeeping genes and Meis with promoter-remote regions and developmental genes. Hox target sequences associate strongly with Meis but not with Prep binding sites, while Pbx1 cooperates with both Prep and Meis. Accordingly, Meis1 shows strong genetic interaction with Pbx1 but not with Prep1. Meis1 and Prep1 nonetheless coregulate a subset of genes, predominantly through opposing effects. Notably, the TALE homeoprotein binding profile subdivides Hox clusters into two domains differentially regulated by Meis1 and Prep1. During evolution, Meis and Prep thus specialized their interactions but maintained significant regulatory coordination.
