Abstract
Haploinsufficiency for human EYA1, a homologue of the Drosophila melanogaster gene eyes absent (eya), results in the dominantly inherited disorders branchio-oto-renal (BOR) syndrome and branchio-oto (BO) syndrome, which are characterized by craniofacial abnormalities and hearing loss with (BOR) or without (BO) kidney defects. To understand the developmental pathogenesis of organs affected in these syndromes, we inactivated the gene Eya1 in mice. Eya1 heterozygotes show renal abnormalities and a conductive hearing loss similar to BOR syndrome, whereas Eya1 homozygotes lack ears and kidneys due to defective inductive tissue interactions and apoptotic regression of the organ primordia. Inner ear development in Eya1 homozygotes arrests at the otic vesicle stage and all components of the inner ear and specific cranial sensory ganglia fail to form. In the kidney, Eya1 homozygosity results in an absence of ureteric bud outgrowth and a subsequent failure of metanephric induction. Gdnf expression, which is required to direct ureteric bud outgrowth via activation of the c-ret Rtk (refs 5, 6, 7, 8), is not detected in Eya1-/- metanephric mesenchyme. In Eya1-/- ear and kidney development, Six but not Pax expression is Eya1 dependent, similar to a genetic pathway elucidated in the Drosophila eye imaginal disc. Our results indicate that Eya1 controls critical early inductive signalling events involved in ear and kidney formation and integrate Eya1 into the genetic regulatory cascade controlling kidney formation upstream of Gdnf. In addition, our results suggest that an evolutionarily conserved Pax-Eya-Six regulatory hierarchy is used in mammalian ear and kidney development.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis*
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Bone and Bones / abnormalities
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Bone and Bones / anatomy & histology
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Bone and Bones / embryology
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Branchio-Oto-Renal Syndrome / genetics
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DNA-Binding Proteins / metabolism
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Ear / abnormalities*
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Ear / anatomy & histology
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Ear / embryology
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Evoked Potentials, Auditory / physiology
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Fibroblast Growth Factor 3
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Fibroblast Growth Factors / metabolism
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Gene Expression Regulation, Developmental
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Glial Cell Line-Derived Neurotrophic Factor
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Hearing Loss, Conductive / metabolism
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Homeodomain Proteins / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins
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Kidney / abnormalities*
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Kidney / anatomy & histology
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Kidney / embryology
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Nerve Growth Factors*
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Nerve Tissue Proteins / metabolism
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Nuclear Proteins*
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PAX2 Transcription Factor
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PAX8 Transcription Factor
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Paired Box Transcription Factors
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Protein Tyrosine Phosphatases
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Proto-Oncogene Proteins / metabolism
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Signal Transduction
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Time Factors
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Trans-Activators / genetics*
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Trans-Activators / metabolism
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Trans-Activators / physiology*
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Transcription Factors / metabolism
Substances
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DNA-Binding Proteins
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FGF3 protein, human
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Fgf3 protein, mouse
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Fibroblast Growth Factor 3
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GDNF protein, human
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Gdnf protein, mouse
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Glial Cell Line-Derived Neurotrophic Factor
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Homeodomain Proteins
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Intracellular Signaling Peptides and Proteins
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Nerve Growth Factors
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Nerve Tissue Proteins
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Nuclear Proteins
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PAX2 Transcription Factor
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PAX2 protein, human
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PAX8 Transcription Factor
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PAX8 protein, human
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Paired Box Transcription Factors
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Pax2 protein, mouse
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Pax8 protein, mouse
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Proto-Oncogene Proteins
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SIX1 protein, human
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Six1 protein, mouse
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Trans-Activators
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Transcription Factors
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Fibroblast Growth Factors
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EYA1 protein, human
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Eya1 protein, mouse
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Protein Tyrosine Phosphatases