A Mutation in Syne2 Causes Early Retinal Defects in Photoreceptors, Secondary Neurons, and Müller Glia

SYNE2 (formerly Nesprin 2 and NUANCE), the second reported member of a family of giant scaffolding proteins,1 is an ortholog of the Drosophila melanogaster muscle protein Msp-300.2 SYNE2 is a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex and is reported to localize to the outer nuclear membrane where it plays a role in connecting the nucleus to the cytoskeleton.3 The amino-terminal calponin homology domains of SYNE2 interact with filamentous actin in the cytosol, whereas its carboxy-terminal conserved Klarsicht, ANC-1, Syne homology (KASH) domain anchors the protein at the nuclear envelope.4 The LINC complex, which also includes emerin, SYNE1, SUN1, SUN2, and lamin A, serves in mechanostructural, signaling and gene regulatory roles in the cell.5 Functional defects in SYNE2 in humans lead to development of Emery-Dreifuss muscular dystrophy as well as dilated cardiomyopathy.6 Targeted null mutations in mice have been shown to affect motor neuron innervation and respiration7 and cause a progeria-like skin phenotype.8 Although not reported in human patients, KASH and SUN domain proteins have been implicated in ocular abnormalities in Drosophila and in zebrafish. In Drosophila, loss of klarsicht (KASH protein homolog) or klaroid (SUN gene homolog) leads to aberrant nuclear migration of photoreceptor nuclei.9,10 Likewise in zebrafish, retinal overexpression of a truncated form of Syne2a lacking the KASH domain also results in mislocalization of photoreceptor nuclei.11,12 Subsequent studies of Syne2 null mouse mutants have reported microcephaly, behavioral abnormalities, and aberrant retinal development including early nuclear migration defects.7,13,14 In the developing retina, interkinetic nuclear migration (INM) is a process by which nuclei of neuroepithelial progenitor cells migrate within the neuroblastic layer (NBL), in coordination with the cell cycle, between the apical and basal surfaces.15,16 Although the purpose of INM is not fully understood, mutations in a number of genes that encode LINC complex proteins, including Syne2, have been shown to disrupt the proper migration of nuclei during development of the retina13,17 and other cell types in tissues such as muscle.6 SYNE2 is highly expressed in developing and adult retinas.18 Early in development, the KASH-specific isoform of SYNE2 localizes homogenously to the nuclear envelope rims throughout the NBL. As the retina matures, expression of the large KASH-specific isoform of SYNE2 is downregulated and undetectable at the photoreceptor nuclear rims. However, Syne2 expression is observed in the photoreceptor inner segments, inner nuclear layer, and ganglion cell layer of adult retinas by in situ analysis. Here we demonstrated that, like the Syne2−/− null mutant,13 homozygous Syne2cpfl8 mice also exhibit an abnormal cone and rod electroretinography (ERG) phenotype and pan-retinal photoreceptor degeneration. Furthermore, we determined that the reduction in cone ERG response results not only from the cell death reported previously13 but, more significantly, from the lack of proper cone development. We also reported a novel finding that horizontal as well as bipolar cells migrate abnormally and form ectopic synapses that may contribute to the observed reduced b-wave amplitudes. In addition, a subset of Muller glial cells also appeared to migrate improperly.