Optic Nerve Hypoplasia Is a Pervasive Subcortical Pathology of Visual System in Neonates

Abstract

PurposeOptic nerve hypoplasia (ONH) is the most common cause of childhood congenital blindness in developed nations, yet the fundamental pathobiology of ONH remains unknown. The objective of this study was to employ a ‘face validated' murine model to determine the timing of onset and the pathologic characteristics of ONH.MethodsBased on the robust linkage between X-linked CASK haploinsufficiency and clinically diagnosed ONH, we hypothesized that heterozygous deletion of CASK (CASK(+/−)) in rodents will produce an optic nerve pathology closely recapitulating ONH. We quantitatively analyzed the entire subcortical visual system in female CASK(+/−) mice using immunohistochemistry, anterograde axonal tracing, toluidine blue staining, transmission electron microscopy, and serial block-face scanning electron microscopy.ResultsCASK haploinsuffiency in mice phenocopies human ONH with complete penetrance, thus satisfying the ‘face validity'. We demonstrate that the optic nerve in CASK(+/−) mice is not only thin, but is comprised of atrophic retinal axons and displays reactive astrogliosis. Myelination of the optic nerve axons remains unchanged. Moreover, we demonstrate a significant decrease in retinal ganglion cell (RGC) numbers and perturbation in retinothalamic connectivity. Finally, we used this mouse model to define the onset and progression of ONH pathology, demonstrating for the first time that optic nerve defects arise at neonatally in CASK(+/−)mice.ConclusionsOptic nerve hypoplasia is a complex neuropathology of the subcortical visual system involving RGC loss, axonopathy, and synaptopathy and originates at a developmental stage in mice that corresponds to the late third trimester development in humans.

An N‐terminal heterozygous missense CASK mutation is associated with microcephaly and bilateral retinal dystrophy plus optic nerve atrophy

“…Relatively preserved function produces microcephaly without any retinal or optic nerve defect, complete loss of function produces ONH, and mutations with functional loss in between the two produces a retinal defect with a delayed onset and thus appears as degenerative changes in childhood. We have shown that CASK haploinsufficiency in mice produces ONH with a reduction in the number of retinal ganglion cells but no change in retinal lamination nor a reduction in the thickness of the photoreceptor cell layer (Liang et al, 2017). Does CASK play a developmental role in the retina outside of the retinal ganglion cells?…”

“…Girls with heterozygous LOF mutations typically exhibit postnatal microcephaly, severe global developmental delays, ponto-cerebellar hypoplasia, motor incoordination, hypotonia, seizures and ophthalmological phenotypes like optic nerve atrophy (ONA) and optic nerve hypoplasia (ONH) (Burglen et al, 2012; Moog et al, 2011). The brain phenotypes seen in humans can be faithfully replicated in female mice by deleting a single allele of the CASK gene, indicating that CASK has a highly conserved role in mammals (Liang et al, 2017; Srivastava et al, 2016).…”

“…Indeed many instances of bilateral ONH (~65%) are also associated with other brain malformations (Ryabets-Lienhard, Stewart, Borchert, & Geffner, 2016). It is not clear, at present, if CASK plays a role in the development of non-RGC retinal cells (Liang et al, 2017).…”

LRRTM1 underlies synaptic convergence in visual thalamus

“…Therefore, based on our results, we hypothesized that LRRTM1-neurexin interactions are critical for the formation of complex RG synapses. Although the necessity of neurexins in retinogeniculate connectivity has yet to be thoroughly examined, the loss of CASK, a MAGUK protein necessary for trafficking neurexins to the presynaptic membrane, leads to abnormal retinogeniculate connectivity and optic nerve hypoplasia ( LaConte et al, 2016 ; Srivastava et al, 2016 ; Moog et al, 2011 ; Liang et al, 2017 ).…”

LRRTM1 underlies synaptic convergence in visual thalamus

“…Therefore, based on our results, we hypothesized that LRRTM1-neurexin interactions are critical for the formation of complex RG synapses. Although the necessity of neurexins in retinogeniculate connectivity has yet to be thoroughly examined, the loss of CASK, a MAGUK protein necessary for trafficking neurexins to the presynaptic membrane, leads to abnormal retinogeniculate connectivity and optic nerve hypoplasia (LaConte et al, 2016, Moog et al, 2011, Liang et al, 2017.…”