Disruptions in abducens nerve development can cause Duane’s retraction syndrome

Abstract

Purpose : Duane’s retraction syndrome (DRS) is characterized by an absent or hypoplastic abducens nerve and aberrant innervation of the lateral rectus muscle by the oculomotor nerve. We developed a new mouse model of DRS to further elucidate its developmental etiology. We provide the first evidence supporting the hypothesis that any insult preventing the abducens nerve from innervating the lateral rectus in development can cause DRS.

Methods : Mafb^WT/flox mice were crossed to the ubiquitously expressing EIIa-cre to generate Mafb^WT/KO mice used for heterozygous crosses, as Mafb^KO/KO mice die at birth. Isl1^MN:GFP reporter mice were crossed in to visualize developing motor axons. Whole mount preparations of embryos at E11.5 were stained with anti-neurofilament, cleared in BABB and imaged by confocal microscopy. Orbits of embryos at E16.5 were dissected, stained with anti-actin α-smooth muscle, cleared in glycerol and imaged by confocal microscopy.

Results : Mafb^KO/KO mice have loss of rhombomeres 5 and 6 in development, absent abducens nerves and nuclei, and fusion of the glossopharyngeal nerves with the vagus nerves. Mafb^WT/KO mice have hypoplastic abducens nuclei and nerves. In the orbits of both Mafb^KO/KO and Mafb^WT/KO mice, the oculomotor nerves aberrantly branch to innervate the lateral recti, recapitulating human DRS. Mafb expression is restricted to the hindbrain in development and therefore Mafb is not expressed in developing oculomotor axons.

Conclusions : We establish Mafb mice as a model for DRS, and demonstrate that specifically disrupting abducens nerve development can cause DRS by allowing the oculomotor nerve to aberrantly innervate the lateral rectus. We provide the first evidence to support the hypothesis that insults to the developing abducens nerve in utero can cause DRS.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

 

Figure 1. (a) In Mafb^WT/WT mice the abducens nerve (arrowhead) innervates the lateral rectus. (b) In Mafb^WT/KO mice a hypoplastic abducens nerve (arrowhead) innervates the lateral rectus, and an aberrant branch of the oculomotor nerve also innervates the lateral rectus (arrow). (c) In Mafb^KO/KO mice the abducens nerve is absent (arrowhead), and the oculomotor nerve aberrantly branches to innervate the lateral rectus (arrow). III, oculomotor; IV, trochlear; VI, abducens; IO, inferior oblique; IR, inferior rectus; LR, lateral rectus; RB, retractor bulbi; scale bar = 100 µm.