Disruption of murine Eml1 results in mislocalization of mitotic neuroblastic cells and early dysplasia of the developing retina

Abstract

Purpose : In humans, loss of EML1, an echinoderm microtubule-associated protein, is associated with defects in the developing brain leading to bilateral giant ribbon-like subcortical heterotopia and hydrocephalus. The primary defect appears to be due to ectopic apical progenitors distributed beyond the cortical proliferative zones and is unlike other forms of heterotopia that typically present with abnormalities in neuronal migration. A chemical mutagenesis screen in the Translational Vision Research Models program identified a murine model, tvrm360, which displayed a novel phenotype of disorganized retinal lamina and cerebral malformations. The purpose of this study was to determine the molecular and pathological basis for the retinal dysplasia observed in tvrm360 mice.

Methods : We used gene mapping and high-throughput sequence analysis to identify the gene responsible for tvrm360. To gain insight into the pathologic and molecular mechanisms underlying the disease in the brain and retina, we assessed tvrm360 and controls longitudinally throughout postnatal development by histological and marker analyses, and by electroretinography and ultrastructural microscopy.

Results : The tvrm360 mutation mapped to chromosome 12, where sequence analysis revealed a premature termination codon in Eml1. At postnatal day 30 (P30), Eml ^tvrm360 displayed severe cerebral malformations and retinal lamination defects: ectopic localization of photoreceptors, and disorganization of secondary neurons and Müller cell bodies. At P0, mitotic cells were displaced within the neuroblastic layer of homozygous Eml1^tvrm360 retinas. Ultrastructural examination at P30 revealed that mislocalized photoreceptor cells in the inner nuclear layer formed cilia and membrane discs, but outer segments failed to form properly. By contrast, photoreceptor cells that were positioned properly in the outer nuclear layer produced normal outer segments.

Conclusions : These findings indicate that EML1 contributes to the proper positioning of progenitor cells during early postnatal retinal development. The results raise the possibility that the Eml1^tvrm360 mutation alters progenitor cell fate by disrupting the postulated role of EML1 in mitotic spindle positioning. Eml1^tvrm360 mice constitute a useful model for studying neuroblastic cell proliferation and spindle/microtubular dynamics in the developing retina.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.