celsr3 is required for normal development of gaba circuits in the inner retinacelsr3 gaba电路的正常发育需要内在的视网膜.pdfVIP

Celsr3 Is Required for Normal Development of GABA Circuits in the Inner Retina 1 1 1 1 2 1 Alaron Lewis , Neil Wilson , George Stearns , Nicolas Johnson , Ralph Nelson , Susan E. Brockerhoff * 1 Department of Biochemistry, University of Washington, Seattle, Washington, United States of America, 2 Basic Neurosciences Program, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Rockville, Maryland, United States of America Abstract The identity of the specific molecules required for the process of retinal circuitry formation is largely unknown. Here we report a newly identified zebrafish mutant in which the absence of the atypical cadherin, Celsr3, leads to a specific defect in the development of GABAergic signaling in the inner retina. This mutant lacks an optokinetic response (OKR), the ability to visually track rotating illuminated stripes, and develops a super-normal b-wave in the electroretinogram (ERG). We find that celsr3 mRNA is abundant in the amacrine and ganglion cells of the retina, however its loss does not affect synaptic lamination within the inner plexiform layer (IPL) or amacrine cell number. We localize the ERG defect pharmacologically to a late-stage disruption in GABAergic modulation of ON-bipolar cell pathway and find that the DNQX-sensitive fast b1 component of the ERG is specifically affected in this mutant. Consistently, we find an increase in GABA receptors on mutant ON-bipolar terminals, providing a direct link between the observed physiological changes and alterations in GABA signaling components. Finally, using blastula transplantation, we show that the lack of an OKR is due, at least partially, to Celsr3- mediated