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BRIEF RESEARCH REPORT article

Front. Cell. Neurosci.
Sec. Cellular Neuropathology
Volume 18 - 2024 | doi: 10.3389/fncel.2024.1474010
This article is part of the Research Topic Celebrating the Year of Ramon y Cajal: Cellular Biology of the Retina View all 14 articles

Loss of Cdc42 causes abnormal optic cup morphogenesis and microphthalmia in mouse

Provisionally accepted
Katrina S. Hofstetter Katrina S. Hofstetter 1Paula M. Haas Paula M. Haas 1Jonathon P. Kuntz Jonathon P. Kuntz 1Yi Zheng Yi Zheng 2Sabine Fuhrmann Sabine Fuhrmann 3*
  • 1 Vanderbilt University Medical Center, Nashville, United States
  • 2 Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, United States
  • 3 Ophthalmology and Visual Sciences, Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States

The final, formatted version of the article will be published soon.

    Congenital ocular malformations originate from defective morphogenesis during early eye development and cause 25% of childhood blindness. Formation of the eye is a multi-step, dynamic process; it involves evagination of the optic vesicle, followed by distal and ventral invagination, leading to the formation of a two-layered optic cup with a transient optic fissure. These tissue folding events require extensive changes in cell shape and tissue growth mediated by cytoskeleton mechanics and intercellular adhesion. We hypothesized that the Rho GTPase Cdc42 may be an essential, convergent effector downstream of key regulatory factors required for ocular morphogenesis. CDC42 controls actin remodeling, apicobasal polarity, and junction assembly. Here we identify a novel essential function for Cdc42 during eye morphogenesis in mouse; in Cdc42 mutant eyes expansion of the ventral optic cup is arrested, resulting in microphthalmia and a wide coloboma. Our analyses show that Cdc42 is required for expression of the polarity effector proteins PRKCZ and PARD6, intercellular junction protein tight junction protein 1, b-catenin, actin cytoskeleton F-actin, and contractile protein phospho myosin light chain 2. Expression of RPE fate determinants OTX2 and MITF, and formation of the RPE layer are severely affected in the temporal domain of the proximal optic cup. EdU incorporation is significantly downregulated. In addition, mitotic retinal progenitor cells mis-localized deeper, basal regions, likely contributing to decreased proliferation. We propose that morphogenesis of the ventral optic cup requires Cdc42 function for coordinated optic cup expansion and establishment of subretinal space, tissue tension, and differentiation of the ventral RPE layer.

    Keywords: Retina, Retinal disease, Microphthalmia, Coloboma, Cdc42, RPE, eye development

    Received: 31 Jul 2024; Accepted: 31 Oct 2024.

    Copyright: © 2024 Hofstetter, Haas, Kuntz, Zheng and Fuhrmann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Sabine Fuhrmann, Ophthalmology and Visual Sciences, Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States

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