Mutant ?2-chimaerin signals via bidirectional ephrin pathways in Duane retraction syndrome.

ABSTRACT: Duane retraction syndrome (DRS) is the most common form of congenital paralytic strabismus in humans and can result from ?2-chimaerin (CHN1) missense mutations. We report a knockin ?2-chimaerin mouse (Chn1KI/KI) that models DRS. Whole embryo imaging of Chn1KI/KI mice revealed stalled abducens nerve growth and selective trochlear and first cervical spinal nerve guidance abnormalities. Stalled abducens nerve bundles did not reach the orbit, resulting in secondary aberrant misinnervation of the lateral rectus muscle by the oculomotor nerve. By contrast, Chn1KO/KO mice did not have DRS, and embryos displayed abducens nerve wandering distinct from the Chn1KI/KI phenotype. Murine embryos lacking EPH receptor A4 (Epha4KO/KO), which is upstream of ?2-chimaerin in corticospinal neurons, exhibited similar abducens wandering that paralleled previously reported gait alterations in Chn1KO/KO and Epha4KO/KO adult mice. Findings from Chn1KI/KI Epha4KO/KO mice demonstrated that mutant ?2-chimaerin and EphA4 have different genetic interactions in distinct motor neuron pools: abducens neurons use bidirectional ephrin signaling via mutant ?2-chimaerin to direct growth, while cervical spinal neurons use only ephrin forward signaling, and trochlear neurons do not use ephrin signaling. These findings reveal a role for ephrin bidirectional signaling upstream of mutant ?2-chimaerin in DRS, which may contribute to the selective vulnerability of abducens motor neurons in this disorder.

SUBMITTER: Nugent AA 

PROVIDER: S-EPMC5409791 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature