CCN–Hippo YAP signaling in vision and its role in neuronal, glial and vascular cell function and behavior

Abstract

The retina is a highly specialized tissue composed of a network of neurons, glia, and vascular and epithelial cells; all working together to coordinate and transduce visual signals to the brain. The retinal extracellular matrix (ECM) shapes the structural environment in the retina but also supplies resident cells with proper chemical and mechanical signals to regulate cell function and behavior and maintain tissue homeostasis. As such, the ECM affects virtually all aspects of retina development, function and pathology. ECM‐derived regulatory cues influence intracellular signaling and cell function. Reversibly, changes in intracellular signaling programs result in alteration of the ECM and downstream ECM‐mediated signaling network. Our functional studies in vitro, genetic studies in mice, and multi omics analyses have provided evidence that a subset of ECM proteins referred to as cellular communication network (CCN) affects several aspects of retinal neuronal and vascular development and function. Retinal progenitor, glia and vascular cells are major sources of CCN proteins particularly CCN1 and CCN2. We found that expression of the CCN1 and CCN2 genes is dependent on the activity of YAP, the core component of the hippo‐YAP signaling pathway. Central to the Hippo pathway is a conserved cascade of inhibitory kinases that regulate the activity of YAP, the final transducer of this pathway. Reversibly, YAP expression and/or activity is dependent on CCN1 and CCN2 downstream signaling, which creates a positive or negative feedforward loop driving developmental processes (e.g., neurogenesis, gliogenesis, angiogenesis, barriergenesis) and, when dysregulated, disease progression in a range of retinal neurovascular disorders. Here we describe mechanistic hints involving the CCN–Hippo–YAP regulatory axis in retina development and function. This regulatory pathway represents an opportunity for targeted therapies in neurovascular and neurodegenerative diseases.

The role of yes activated protein (YAP) in melanoma metastasis

“… 100 , 101 Including in melanoma cells, CCN1 and CCN2 expression is induced by TGFβ, RAS/MEK/ERK, hypoxia and mechanotransduction; indeed, they are considered prototypical YAP targets. 13 , 14 , 102 , 103 , 104 , 105 , 106 , 107 CCN1 and CCN2 are pro-adhesive and signal through a variety of integrin heterodimers to promote angiogenic and ECM programs in vivo and in vitro . 108 , 109 , 110 , 111 , 112 Mice postnatally deleted for either CCN1 or CCN2 in collagen-lineage fibroblasts are resistant to the syngeneic B16F10 model of melanoma metastasis.…”

CCNs and other extracellular matrix proteins: an introduction to the special issue

“…In retinal neuronal and vascular development and function, various CCN proteins play essential function. The review by Chaqour (2023) highlights the role of the The extracellular matrix (ECM) is a specialized, highly organized and dynamic three-dimensional network composed of a complex mixture of proteins and other molecules forming the physical scaffolding of a cell and determining the tissue architecture of organs (Rais et al, 2023). It is of fundamental importance in cell growth, cell migration, and cellular communication.…”