Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia

Haploinsufficiency for human EYA1, a homologue of the Drosophila melanogast er gene eyes absent (eya), results in the dominantly inherited disorders br anchio-oto-renal (BOR) syndrome(1-3) and branchio-oto (BO) syndrome(4), whi ch are characterized by craniofacial abnormalities and hearing loss with (B OR) or without (BO) kidney defects. To understand the developmental pathoge nesis of organs affected in these syndromes, we inactivated the gene Eya1 i n mice. Eya1 heterozygotes show renal abnormalities and a conductive hearin g loss similar to BOR syndrome, whereas Eya1 homozygotes lack ears and kidn eys 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 resu lts in an absence of ureteric bud outgrowth and a subsequent failure of met anephric induction. Gdnf expression, which is required to direct ureteric b ud outgrowth via activation of the c-ret Rtk (refs 5-8), 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 an d kidney formation and integrate Eya1 into the genetic regulatory cascade c ontrolling kidney formation upstream of Gdnf. In addition, our results sugg est that an evolutionarily conserved Pax-Eya-Six regulatory hierarchy is us ed in mammalian ear and kidney development.