Determinants of extraocular motor neuron subtype diversity

PROJECT SUMMARY / ABSTRACT Developmental disorders of the ocular motor system can lead to misalignment of the eyes called strabismus. Mutations in genes responsible for extraocular motor neuron fate specification (e.g. PHOX2A and MAFB) and axonal outgrowth (e.g. KIF21A and TUBB2B cause congenital incomitant (gaze angle dependent) strabis- mus. However, although strabismus is heritable, only a few such genes have been identified. Consequentially, causative genes for most forms of congenital incomitant strabismus are unknown. We propose to pair discov- ery and hypothesis-driven approaches to (1) define genetic determinants of key aspects of extraocular motor neuron development and (2) understand the behavioral and anatomical consequences of their disruption. Extraocular motor neurons can be classified into subtypes along three lines: developmental time (early vs. late); anatomy (muscle innervation), and function (fast/slow). Here we propose to use a small model verte- brate, the larval zebrafish, to define the genes that determine subtype fate specification and control axon out- growth/muscle innervation in developing extraocular motor neurons. Aim 1 will build on our existing pipelines and preliminary data to establish an atlas of longitudinal transcriptional profiles from defined subtypes of ex- traocular motor neurons. Next, Aim 2 will mine and validate transcriptional data to select candidate determi- nants of extraocular motor neuron subtype fate and muscle innervation. Finally, Aim 3 will test hypotheses of candidate gene function by measuring behavioral, functional, anatomical, and transcriptional phenotypes that follow loss of function. By defining genetic determinants of extraocular motor neuron subtypes we take a signifi- cant step towards understanding both normal and disordered ocular motor development.