Mkk4 and Mkk7 are important for retinal development and axonal injury-induced retinal ganglion cell death

Abstract

The mitogen activated protein kinase (MAPK) pathway has been shown to be involved in both neurodevelopment and neurodegeneration. c-Jun N-terminal kinase (JNK), a MAPK shown to be important in retinal development and after optic nerve crush injury, is regulated by two upstream kinases: MKK4 and MKK7. The specific requirements of MKK4 and MKK7 in retinal development and retinal ganglion cell (RGC) death after axonal injury, however, are currently undefined. Optic nerve injury is an important insult in many neurologic conditions including traumatic, ischemic, inflammatory, and glaucomatous optic neuropathies. Mice deficient in Mkk4, Mkk7, and both Mkk4 and Mkk7 were generated. Immunohistochemistry was used to study the distribution and structure of retinal cell types and to assess RGC survival after optic nerve injury (mechanical controlled optic nerve crush; CONC). Adult Mkk4 and Mkk7 deficient retinas had all retinal cell types. With the exception of small areas of lamination defects with photoreceptors in Mkk4 deficient mice, the retinas of both mutants were grossly normal. Deficiency of Mkk4 or Mkk7 reduced JNK signaling after axonal injury in RGCs. Mkk4 and Mkk7 deficient retinas had a significantly greater percentage of surviving RGCs 35 days after CONC as compared to wildtype controls (Mkk4: 51.5%, Mkk7: 29.1% WT: 15.2%; p<0.001). Combined deficiency of Mkk4 and Mkk7 caused failure of optic nerve formation, irregular retinal axonal trajectories, disruption of retinal lamination, clumping of RGC cell bodies, and dendritic fasciculation of dopaminergic amacrine cells. These results suggest that MKK4 and MKK7 may serve redundant and unique roles in molecular signaling important for retinal development and injury response following axonal insult.