Journal of Neoplasm

Description

In the process of locally designing the front brain plate, a cluster of cells centrally positioned is identified as housing retinal characteristics. These specialized eye field cells undergo distinct morphogenetic events compared to other regions of the forebrain. Our study reveals that two components of the Wnt signaling pathway orchestrate both cell fate determination and behavior during the formation of the eye field. During the development of the Central Nervous System (CNS), regional fate determination must be intricately linked with the morphogenetic processes shaping various brain structures. Among vertebrates, the intricacies of this integration are particularly evident in the highly specialized organ of vision. The optic vesicles emerge as outgrowths of the forebrain, but prior to this, a cohesive group of cells destined to form the eyes exists as a distinct bilateral domain known as the eye field. This eye field is readily identifiable within the anterior brain plate by the coordinated expression of several key genes constituting the eye determination network. During gastrulation, the Anterior Neural Plate (ANP) undergoes segmentation into domains giving rise to telencephalic, eye field, diencephalic and hypothalamic fates.

Cellular stresses

Wnt/β-catenin signaling disrupts eye specification through the action of Wnt8b and Fz8a. Conversely, Wnt11 and Fz5 promote the development of the eye field, in part, by locally antagonizing Wnt/β-catenin signaling. Additionally, Wnt11 influences the behavior of eye field cells, facilitating their cohesion. These findings lead us to propose a model where Wnt11 and Fz5 signaling facilitate early eye development by orchestrating a balanced interplay of signals that suppress retinal identity while ensuring the stability of eye field cells. In this study, we delve into the mechanisms through which Wnt signaling regulates the early stages of eye field development. We discover that two components of the Wnt pathway significantly influence eye development. Elevated levels of Wnt/β-catenin signaling are necessary for acquiring caudal diencephalic fate and disrupt eye induction. Additionally, Wnt11 signaling enhances coherence of eye field cells, potentially contributing to the coordinated morphogenetic behaviors of cells in the early eye field. Each aspect of the Wnt pathway appears to be activated by a different combination of Wnt/Fz receptors in the early forebrain.

Wnt signaling

Inactivation of the GSK3β/axin/β-catenin complex upon pathway activation leads to accumulation and nuclear translocation of β-catenin, where it interacts with transcription factors such as Lymphoid Enhancer binding Factor 1 (LEF1) or TCell Factor (TCF) to modulate transcription. Various proteins regulate the activity of the pathway, including the cytoplasmic protein tousled, which collaborates with pathway activation upon ligand/receptor binding. Wnts can also activate alternative signaling cascades, including one branch shared with the planar cell polarity pathway observed in drosophila. Non-canonical Wnt pathways are GSK3β/axin/APC- and β-catenin-independent but share components with the Wnt/β-catenin pathway, such as Disheveled (Dsh).

Depending on the context, activation of β-cateninindependent Wnt signaling may involve intracellular calcium release, small GTPases of the Rho family and activation of the JNK signaling cascade, ultimately influencing cytoskeletal organization and cellular polarity as well as behavior. In vertebrates, non-canonical Wnt signaling has been extensively studied for its role in regulating the convergence and extension movements of mesodermal cells during gastrulation, shaping the embryo. The vertebrate genome encodes numerous Wnt ligands, which generally exhibit selective activation of either β-catenindependent or β-catenin-independent pathways. The mechanism underlying the specificity of each ligand for a particular aspect of the Wnt pathway remains unclear, as does whether different Wnts have specific Frizzled partners.

A widely favored model of early brain patterning suggests that a gradient of Wnt/β-catenin activity specifies different regional fates, with higher levels of signaling promoting more caudal brain identities. This leads to the establishment of more localized sources of Wnts and Wnt antagonists, which in turn refine regional patterning. Within the forebrain, evidence from studies in mice, chicks and fish supports the notion that Wnt/β-catenin signaling promotes caudal diencephalic identity and that elevated levels of signaling can suppress more rostral forebrain fates. For instance, in zebrafish, the establishment of telencephalic identity requires the suppression of high levels of Wnt/β-catenin signaling, whereas the establishment of diencephalic identity is promoted by elevated levels of Wnt/β- catenin signaling.