Cell-specific roles for CASK in the pathology of Optic Nerve Hypoplasia

Optic Nerve Hypoplasia (ONH) is the leading cause of childhood blindness in developed nations and its prevalence has been rising. Yet, we know little about the genetic, molecular, or cellular mechanisms underlying ONH. A previous study described ONH in a cohort of patients with mutations in CASK, an X-linked gene with established roles in neural development and synaptic function. I have demonstrated that heterozygous deletion of CASK in mice (Cask+/-) recapitulates many of the phenotypes observed in patients with CASK mutations, including ONH. This includes reduced optic nerve size, reduced numbers of retinal ganglion cells (RGCs), reduced RGC axonal diameter, and deficits in vision-related tasks. Further analysis on a homozygous partial loss of function variant (Caskfl/fl) also displayed ONH with reduced numbers of RGCs. In order to understand the mechanisms underlying CASK-associated ONH, I explored whether RGCs, the projection neurons of the retina and the cells whose axons comprise the optic nerve, generate CASK. Indeed, mRNA analysis revealed expression of CASK by a large cohort of RGCs. In order to assess whether loss of CASK from a majority of RGCs leads to ONH, I crossed a conditional allele of CASK (CASKfl/fl) with transgenic mice that express Cre Recombinase (Cre) in RGCs. Deletion of CASK from RGCs did not further alter ONH size nor RGC survival. These results demonstrate that loss of CASK signaling in this discrete neuronal populations is not sufficient to lead to further disruption in the assembly of the subcortical visual circuit, suggesting a non-cell autonomous mechanism for loss of CASK in ONH.