Functional specialization of retinal Muller cell endfeet depends on an interplay between two syntrophin isoforms.

Retinal Muller cells are highly polarized macroglial cells with accumulation of the aquaporin-4 (AQP4) water channel and the inwardly rectifying potassium channel Kir4.1 at specialized endfoot membrane domains abutting microvessels and corpus vitreum. Proper water and potassium homeostasis in retina depends on these membrane specializations. Here we show that targeted deletion of beta1-syntrophin leads to a partial loss of AQP4 from perivascular Muller cell endfeet and that a concomitant deletion of both alpha1- and beta1-syntrophin causes a near complete loss of AQP4 from both perivascular and subvitreal endfoot membranes. alpha1-syntrophin is normally very weakly expressed in Muller cell endfeet but beta1-syntrophin knockout mice display an increased amount of alpha1-syntrophin at these sites. We suggest that upregulation of perivascular alpha1-syntrophin restricts the effect of beta1-syntrophin deletion. The present findings indicate that beta1-syntrophin plays an important role in maintaining the functional polarity of Muller cells and that alpha1-syntrophin can partially substitute for beta1-syntrophin in AQP4 anchoring. Functional polarization of Muller cells thus depends on an interplay between two syntrophin isoforms.