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

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) syndrome1,2,3 and branchio-oto (BO) syndrome4, 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.

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Figure 1: ABR threshold measurements and pathological structures in Eya1+/– ears.
Figure 2: Skeletal abnormalities in Eya1 homozygotes.
Figure 3: Auditory system development in Eya1–/– mice.
Figure 4: Molecular defects during otic development in Eya1 homozygotes.
Figure 5: Kidney development in Eya1 homozygotes.
Figure 6: Molecular defects during metanephric development in Eya1–/– mice.

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Acknowledgements

We thank A. Sharpe and L. Du for blastocyst injections; P. Leder and C. O'Hara for help with ES cell transfections; D. Beier for the 129/SvJ BAC library; A. Yoon, A. Iwasaki and H. Dushkin for technical assistance; and T. Natoli and J. Kreidberg for providing a mouse Wt1 in situ probe. This work was supported by NIH RO1 EY10123 and RO1 DE11697 (R.M.) and NRSA F32 EY006869 (P.-X.X.).

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Correspondence to Richard Maas.

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Xu, PX., Adams, J., Peters, H. et al. Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia. Nat Genet 23, 113–117 (1999). https://doi.org/10.1038/12722

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