Abstract
Down Syndrome Cell Adhesion Molecules (dscam and dscaml1) are essential regulators of neural circuit assembly, but their roles in vertebrate neural circuit function are still mostly unexplored. We investigated the role of dscaml1 in the zebrafish oculomotor system, where behavior, circuit function, and neuronal activity can be precisely quantified. Loss of zebrafish dscaml1 resulted in deficits in retinal patterning and light adaptation, consistent with its known roles in mammals. Oculomotor analyses showed that mutants have abnormal gaze stabilization, impaired fixation, disconjugation, and faster fatigue. Notably, the saccade and fatigue phenotypes in dscaml1 mutants are reminiscent of human ocular motor apraxia, for which no animal model exists. Two-photon calcium imaging showed that loss of dscaml1 leads to impairment in the saccadic premotor pathway but not the pretectum-vestibular premotor pathway, indicating a subcircuit requirement for dscaml1. Together, we show that dscaml1 has both broad and specific roles in oculomotor circuit function, providing a new animal model to investigate the development of premotor pathways and their associated human ocular disorders.
Footnotes
Conflict of Interest: J.K.J. has financial interests in Beam Therapeutics, Editas Medicine, Pairwise Plants, Poseida Therapeutics, Transposagen Biopharmaceuticals, and Verve Therapeutics. J.K.J.’s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. J.K.J. holds equity in Excelsior Genomics. J.K.J. is a member of the Board of Directors of the American Society of Gene and Cell Therapy. J.K.J. is a co-inventor on various patents and patent applications that describe gene editing and epigenetic editing technologies.