PgmNr Z6212: Retinal patterning and saccadic eye movements in Zebrafish require Down Syndrome Cell Adhesion Molecule-Like 1.

Authors:
Tong Wang 1 ; Manxiu Ma 1 ; Avirale Sharma 1 ; Christopher Kuang 1,7 ; Rachel Roberts 1,8 ; James A. Gagnon 2 ; Andrea Pauli 2 ; Steve Zimmerman 2 ; Shengdar Q. Tsai 3,4 ; Deepak Reyon 3,4 ; J. Keith Joung 3,4,5 ; Alexander F. Schier 2 ; Y. Albert Pan 1,6


Institutes
1) Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta Univ., Augusta, GA; 2) Department of Molecular and Cellular Biology, Harvard Stem Cell Institute, Center for Brain Science, Harvard Univ., Cambridge, MA; 3) Molecular Pathology Unit, Center for Computational and Integrative Biology, and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA; 4) Department of Pathology, Harvard Medical School, Boston, MA; 5) The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA; 6) Department of Neurology, James & Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta Univ., Augusta, GA; 7) Medical Scholars Program; 8) Graduate Program in Neuroscience.


Abstract:

Down syndrome cell adhesion molecule (Dscam) family genes play diverse roles across many species. The Drosophila dscam is alternatively spliced and serves as intra- and intercellular recognition cues for repulsive interactions between axons and dendrites. In mice and chicken,  Dscam and Dscam-like 1 (Dscaml1) are involved in promoting cell death, maintain cellular spacing, and laminar targeting of neurites in the developing visual system. The functional and behavioral importance of Dscam and Dscaml1, however, are less clear. In this study, we generated a TALEN-mediated dscaml1 mutant in Zebrafish (Danio rerio) and investigated how loss of dscaml1 affects visual system development and visual behaviors. The small size, translucent brain, powerful genetics, and robust visual behaviors of zebrafish make it an ideal vertebrate model system. Consistent with dscaml1’s function in mammals, we found significant aggregation and misplacement of retinal cell types, particularly the serotonergic amacrine cells and muller glia. The mutant brain was narrower, with increased neuropil thickness and reduced width. Despite these abnormalities, dscaml1 have normal light-on and light-off induced locomotor response and can respond to moving vertical bars while performing the optokinetic response (OKR), suggesting that perception of visual stimulus is grossly normal, though light sensitivity is reduced. However, when challenged with a faster or more prolonged moving stimulus, the dscaml1 mutants display severe deficits in saccadic (fast-resetting) eye movements and the eyes eventually become fixated at eccentric positions. These results suggest that dscaml1 is required for the development or function of the motor systems downstream of saccade generation centers. Work is currently in progress to investigate the neural correlates of the saccade deficits and the temporal requirements of dscaml1.



ZFIN Genetics Index
1. dscaml1