Mind Bomb-Binding Partner RanBP9 Plays a Contributory Role in Retinal Development

Abstract

Ran-binding protein family member, RanBP9 has been reported in various basic cellular mechanisms and neuropathological conditions including schizophrenia. Previous studies have reported that RanBP9 is highly expressed in the mammalian brain and retina; however, the role of RanBP9 in retinal development is largely unknown. Here, we present the novel and regulatory roles of RanBP9 in retinal development of a vertebrate animal model, zebrafish. Zebrafish embryos exhibited abundant expression of ranbp9 in developing brain tissues as well as in the developing retina. Yeast two-hybrid screening demonstrated the interaction of RanBP9 with Mind bomb, a component of Notch signaling involved in both neurogenesis and neural disease autism. The interaction is further substantiated by co-localization studies in cultured cells. Knockdown of ranbp9 resulted in retinal dysplasia with defective proliferation of retinal cells, downregulation of neuronal differentiation marker huC, elevation of neural proliferation marker her4, and alteration of cell cycle marker p57kip2. Expression of the Müller glial cell marker glutamine synthase was also affected in knockdown morphants. Our results suggest that Mind bomb-binding partner RanBP9 plays a role during retinal cell development of zebrafish embryogenesis.

Structural and Functional Insights into GID/CTLH E3 Ligase Complexes

“…Deficiency of both Rmnd5 and wdr26 caused a forebrain formation impairment and reduction in the same neural marker, pax6 [ 52 , 97 ]. In zebrafish embryos, RanBP9 expression is also highest in the neural regions and its deficiency caused defects in brain development and retinogenesis [ 103 ]. Strikingly, several reports showed that global RanBP9 −/− mice have neonatal lethality and postnatal growth inhibition, due at least in part to a compromised somatosensory system [ 101 , 102 , 104 ].…”

The Regulation of Notch Signaling in Retinal Development and Regeneration

“…RanBP9 is an adaptor protein which helps to bridge membrane bound receptors with intracellular components that regulate the signaling of the receptors, and has been implicated in the regulation of brain development [33]. In the zebrafish retina, RanBP9 has been identified as a binding partner of mindbomb, facilitating the interaction with the intracellular domain of the Notch ligand, delta, necessary for delta’s internalization [34]. Similar to the mindbomb mutant, loss of RanBP9 results in defective proliferation and premature neuronal differentiation in the retina.…”