Deletion of a remote enhancer near ATOH7 disrupts retinal neurogenesis, causing NCRNA disease
Copyright policy )Deletion of a remote enhancer near ATOH7 disrupts retinal neurogenesis, causing NCRNA disease
Individuals with nonsyndromic congenital retinal nonattachment (NCRNA) are totally blind from birth. The disease afflicts ∼1% of Kurdish people living in a group of neighboring villages in North Khorasan, Iran. We found that NCRNA is caused by a 6,523-bp deletion that spans a remote cis regulatory element 20 kb upstream from ATOH7 (Math5), a bHLH transcription factor gene that is required for retinal ganglion cell (RGC) and optic nerve development. In humans, the absence of RGCs stimulates massive neovascular growth of fetal blood vessels in the vitreous and early retinal detachment. The remote ATOH7 element appears to act as a secondary or 'shadow' transcriptional enhancer. It has minimal sequence similarity to the primary enhancer, which is close to the ATOH7 promoter, but drives transgene expression with an identical spatiotemporal pattern in the mouse retina. The human transgene also functions appropriately in zebrafish, reflecting deep evolutionary conservation. These dual enhancers may reinforce ATOH7 expression during early critical stages of eye development when retinal neurogenesis is initiated.
- Department of Biology United States
- University of Michigan–Ann Arbor United States
- UNIVERSITY OF MICHIGAN
- University of California, San Francisco United States
- University of Michigan United States
Male, DNA Mutational Analysis, Iran, Eye, Animals, Genetically Modified, Mice, Consanguinity, Basic Helix-Loop-Helix Transcription Factors, Psychology, Developmental, Pair 10, Child, Zebrafish, Ophthalmology and Optometry, Sequence Deletion, Chromosome Mapping, Gene Expression Regulation, Developmental, Single Nucleotide, Middle Aged, Flow Cytometry, Magnetic Resonance Imaging, Enhancer Elements, Genetic, Embryo, Child, Preschool, Cognitive Sciences, Female, Human, Superior Colliculi, Enhancer Elements, Adolescent, Neurogenesis, Genetically Modified, Chromosomes, Retina, Article, Genetic, Genetics, Animals, Humans, Polymorphism, Preschool, Eye Disease and Disorders of Vision, Family Health, Neurology & Neurosurgery, Biomedical and Clinical Sciences, Chromosomes, Human, Pair 10, Mammalian, Neurosciences, Retinal Detachment, Computational Biology, Embryo, Mammalian, Luminescent Proteins, Gene Expression Regulation, Biological psychology
Male, DNA Mutational Analysis, Iran, Eye, Animals, Genetically Modified, Mice, Consanguinity, Basic Helix-Loop-Helix Transcription Factors, Psychology, Developmental, Pair 10, Child, Zebrafish, Ophthalmology and Optometry, Sequence Deletion, Chromosome Mapping, Gene Expression Regulation, Developmental, Single Nucleotide, Middle Aged, Flow Cytometry, Magnetic Resonance Imaging, Enhancer Elements, Genetic, Embryo, Child, Preschool, Cognitive Sciences, Female, Human, Superior Colliculi, Enhancer Elements, Adolescent, Neurogenesis, Genetically Modified, Chromosomes, Retina, Article, Genetic, Genetics, Animals, Humans, Polymorphism, Preschool, Eye Disease and Disorders of Vision, Family Health, Neurology & Neurosurgery, Biomedical and Clinical Sciences, Chromosomes, Human, Pair 10, Mammalian, Neurosciences, Retinal Detachment, Computational Biology, Embryo, Mammalian, Luminescent Proteins, Gene Expression Regulation, Biological psychology
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