The importance of Foxi1 expression in kidney and inner ear

The forkhead (FOX) genes comprise a family of transcription factors involved in generegulation in both embryonic and adult tissue. Foxi1 is expressed in the kidney andthe developing inner ear. We examined the significance of Foxi1 in these two organsand explain the molecular mechanisms behind the phenotype seen in Foxi1 deficientmice.The kidney collecting duct epithelium is heterogeneous, composed of intercalatedand principal cells. By dual labelling of kidney sections with Foxi1 cRNA in situhybridisation and immunostaining with various kidney collecting duct cell markers,we localised Foxi1 expression exclusively to intercalated cells. Foxi1 deficientcollecting ducts have lost the expression of several proteins involved in bicarbonateor proton transport. Transmission electron microscopy of collecting ducts revealedthat the epithelium from Foxi1 null tubules was homogeneous and completely lackeda protruding, microvilli-rich cell type. Instead, this epithelium was found to becomposed of a single cell type that expressed both principal (aquaporin 2) andintercalated (carbonic anhydrase II) cell markers. This hybrid cell is unable tomaintain systemic acid/base homeostasis and Foxi1 deficiency consequently resultsin distal renal tubular acidosis.Foxi1 and the co-activator Eya1 are expressed in the developing inner ear. The earlymorphogenesis and patterning of the otic vesicle (OV) in Foxi1 deficient mice appearto proceed normally, while Eya1 deficiency leads to an arrest in development at theOV stage. Our results indicate that Eya1 is required for the establishment of regionalspecification of the OV. Eya1 also regulates Bmp- and Fgf-signalling pathways duringearly inner ear development. At E16.5, Foxi1 is exclusively expressed in theendolymphatic duct and sac. Without Foxi1, the inner ear develops an endolymphaticepithelium with no FORE cells. The loss of this cell type and consequently the genesnormally expressed here, leads to defective endolymph fluid handling and inner earexpansion. This causes rupture of inner ear membranes that makes it impossible topreserve an endocochlear potential and the Foxi1 deficient mice therefore becomedeaf.In summary, Foxi1 is significant for complete maturation of the collecting duct andendolymphatic duct and sac epithelia, including the formation of the intercalated andFORE cells, which are responsible for acid/base regulation. Our data suggest thatmutations in human FOXI1 might cause a sensorineural deafness syndrome withdistal renal tubular acidosis