Identification of MFRP and the secreted serine proteases PRSS56 and ADAMTS19 as part of a molecular network involved in ocular growth regulation

Author summary During ocular refractive development, the eye's growth is modulated, such that the ocular axial length matches the optical power enabling the eyes to achieve optimal focus. Alterations in ocular growth mainly contribute to refractive errors. Mutations in human PRSS56 and MFRP are responsible for nanophthalmos that exhibit a severe reduction in ocular axial length, and high hyperopia. Importantly, mutant mouse models lacking either Muller glia expressed PRSS56, or retinal pigment epithelium (RPE) localized MFRP exhibit ocular axial length reduction. Here, we have identified Adamts19 as a factor whose levels were significantly upregulated in the retina of mice lacking either Prss56 or Mfrp. Importantly, utilizing Adamts19 knockout mice we demonstrate that upregulation of retinal Adamts19 expression constitutes a compensatory mechanism that provides partial protection against ocular axial reduction due to mutation in Prss56 and Mfrp. Next, utilizing a mouse model of early-onset myopia, we demonstrate that the mutant Irbp induced ocular axial elongation is completely dependent on Prss56 as well as Mfrp, suggesting an interplay between Muller glia and RPE in the regulation of ocular axial growth. Collectively, these findings suggest that ocular refractive development relies on complex interactions occurring between genetic factors in the retina and RPE. Precise regulation of ocular size is a critical determinant of normal visual acuity. Although it is generally accepted that ocular growth relies on a cascade of signaling events transmitted from the retina to the sclera, the factors and mechanism(s) involved are poorly understood. Recent studies have highlighted the importance of the retinal secreted serine protease PRSS56 and transmembrane glycoprotein MFRP, a factor predominantly expressed in the retinal pigment epithelium (RPE), in ocular size determination. Mutations in PRSS56 and MFRP constitute a major cause of nanophthalmos, a condition characterized by severe reduction in ocular axial length/extreme hyperopia. Interestingly, common variants of these genes have been implicated in myopia, a condition associated with ocular elongation. Consistent with these findings, mice with loss of function mutation in PRSS56 or MFRP exhibit a reduction in ocular axial length. However, the molecular network and cellular processes involved in PRSS56- and MFRP-mediated ocular axial growth remain elusive. Here, we show that Adamts19 expression is significantly upregulated in the retina of mice lacking either Prss56 or Mfrp. Importantly, using genetic mouse models, we demonstrate that while ADAMTS19 is not required for ocular growth during normal development, its inactivation exacerbates ocular axial length reduction in Prss56 and Mfrp mutant mice. These results suggest that the upregulation of retinal Adamts19 is part of an adaptive molecular response to counteract impaired ocular growth. Using a complementary genetic approach, we show that loss of PRSS56 or MFRP function prevents excessive ocular axial growth in a mouse model of early-onset myopia caused by a null mutation in Irbp, thus, demonstrating that PRSS56 and MFRP are also required for pathological ocular elongation. Collectively, our findings provide new insights into the molecular network involved in ocular axial growth and support a role for molecular crosstalk between the retina and RPE involved in refractive development.

Automated summary

This study reveals the complex interactions between genetic factors in the retina and RPE in ocular refractive development, with Adamts19 as a compensatory mechanism for ocular axial length reduction. PRSS56 and MFRP are crucial for pathological ocular elongation, and the upregulation of retinal Adamts19 serves as an adaptive molecular response to impaired ocular growth.