Chen Liang1,2, Alicia Kerr1,3, Yangfengzhong Qiu1, Francesca Cristofoli4, Hilde Van Esch4, Michael A Fox1,2, Konark Mukherjee1,2. 1. Developmental and Translational Neurobiology Center, Virginia Tech Carilion Research Institute, Roanoke, Virginia, United States. 2. Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, United States. 3. Graduate Program in Translational Biology, Medicine, and Health, Virginia Tech, Blacksburg, Virginia, United States. 4. Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
Abstract
Purpose: Optic 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. Methods: Based 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. Results: CASK 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. Conclusions: Optic 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.
Purpose: Optic 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. Methods: Based 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. Results:CASK 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. Conclusions: Optic 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.
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Authors: P A Patel; C Liang; A Arora; S Vijayan; S Ahuja; P K Wagley; R Settlage; L E W LaConte; H P Goodkin; I Lazar; S Srivastava; K Mukherjee Journal: Exp Neurol Date: 2020-04-17 Impact factor: 5.330
Authors: Aboozar Monavarfeshani; Gail Stanton; Jonathan Van Name; Kaiwen Su; William A Mills; Kenya Swilling; Alicia Kerr; Natalie A Huebschman; Jianmin Su; Michael A Fox Journal: Elife Date: 2018-02-09 Impact factor: 8.140
Authors: Alicia Kerr; Paras A Patel; Leslie E W LaConte; Chen Liang; Ching-Kang Chen; Veeral Shah; Michael A Fox; Konark Mukherjee Journal: Invest Ophthalmol Vis Sci Date: 2019-08-01 Impact factor: 4.799