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Marina Han, Ighovie F. Onojafe, Mariya R. Ahmed, Maria M Campos, Temesgen D Fufa, Tiziana Cogliati, Mones S Abu-Asab, Brian Brooks, Robert Hufnagel; Investigating the role of Kit in ocular melanocyte development and vision. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4315.
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© ARVO (1962-2015); The Authors (2016-present)
The receptor tyrosine kinase KIT is expressed in ocular melanocytes and plays a role in signaling pathways for cell survival, proliferation, migration, and melanocyte specification and differentiation. Whether ocular pigmentation defects associated with KIT deficiency are due to failure of melanocyte development or maintenance is unclear. Further, no function of KIT in retinal pigment epithelium (RPE) development or vision is known. We examined the role of the mouse homologue Kit in ocular melanocyte and RPE development, and whether melanocytes are required for normal eye development and vision.
The mouse KitW-v allele substitutes methionine for threonine at position 660. We studied the ocular structure and function of Kit+/+, KitW-v/+, and KitW-v/W-v mice aged 3-9.5 months. Structural integrity and pigmentation were evaluated using histology, electron microscopy (EM), and optical coherence tomography (OCT). Visual function was assessed through quantitative optomotor response (qOMR). Data was analyzed in GraphPad Prism.
Histological characterization of retinal tissue suggested that KitW-v/W-v have decreased choroidal melanocyte pigmentation compared to KitW-v/+ and Kit+/+. EM showed that choroidal melanocytes lacked melanosomes and exhibited overall degeneration, while RPE contained degenerate mitochondria, lacked apical processes, and lost melanosomes to surrounding tissue. On OCT, we saw no quantifiable difference in retina, retina-RPE, and retina-choroid thicknesses between genotypes. Functionally, young Kit+/+ and KitW-v/W-v did not significantly differ in qOMR, but both showed an age-related decline, with aged KitW-v/W-v performing worse than aged Kit+/+ mice. To understand whether the RPE phenotype in KitW-v/W-v mice is cell-autonomous or non-autonomous, we are currently analyzing primary mouse RPE cells in vitro.
Diminished Kit function causes pigmentation loss, choroidal melanocyte degeneration, and a degenerative RPE phenotype, which are associated with a more severe age-related decline in vision for KitW-v/W-v compared to Kit+/+ mice. Future research will determine whether multiple longitudinal modalities confirm the age-related changes in vision and seek to clarify the contributions of choroidal melanocyte versus RPE development to this phenotype. Ultimately, these efforts will advance our understanding of the potential roles of KIT in human eye development and disease.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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